Neuromuscular Disorders

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

When I was a child, I watched syndicated episodes of the original “Star Trek.” I was dazzled by the space travel, sure, but also the medical technology.

A handheld “tricorder” detected diseases, while an intramuscular injector (“hypospray”) could treat them. Sickbay “biobeds” came with real-time health monitors that looked futuristic at the time but seem primitive today.

Such visions inspired a lot of us kids to pursue science. Little did we know the real-life advances many of us would see in our lifetimes.

Artificial intelligence helping to spot disease, robots performing surgery, even video calls between doctor and patient – all these once sounded fantastical but now happen in clinical care.

Now, in the 23rd year of the 21st century, you might not believe wht we’ll be capable of next. Three especially wild examples are moving closer to clinical reality. 
 

Human hibernation

Captain America, Han Solo, and “Star Trek” villain Khan – all were preserved at low temperatures and then revived, waking up alive and well months, decades, or centuries later. These are fictional examples, to be sure, but the science they’re rooted in is real.

Rare cases of accidental hypothermia prove that full recovery is possible even after the heart stops beating. The drop in body temperature slows metabolism and reduces the need for oxygen, stalling brain damage for an hour or more. (In one extreme case, a climber survived after almost 9 hours of efforts to revive him.)

Useful for a space traveler? Maybe not. But it’s potentially huge for someone with life-threatening injuries from a car accident or a gunshot wound.

That’s the thinking behind a breakthrough procedure that came after decades of research on pigs and dogs, now in a clinical trial. The idea: A person with massive blood loss whose heart has stopped is injected with an ice-cold fluid, cooling them from the inside, down to about 50° F.

Doctors already induce more modest hypothermia to protect the brain and other organs after cardiac arrest and during surgery on the aortic arch (the main artery carrying blood from the heart).

But this experimental procedure – called emergency preservation and resuscitation (EPR) – goes far beyond that, dramatically “decreasing the body’s need for oxygen and blood flow,” says Samuel Tisherman, MD, a trauma surgeon at the University of Maryland Medical Center and the trial’s lead researcher. This puts the patient in a state of suspended animation that “could buy time for surgeons to stop the bleeding and save more of these patients.”

The technique has been done on at least six patients, though none were reported to survive. The trial is expected to include 20 people by the time it wraps up in December, according to the listing on the U.S. clinical trials database. Though given the strict requirements for candidates (emergency trauma victims who are not likely to survive), one can’t exactly rely on a set schedule.

Still, the technology is promising. Someday we may even use it to keep patients in suspended animation for months or years, experts predict, helping astronauts through decades-long spaceflights, or stalling death in sick patients awaiting a cure.
 

Artificial womb

Another sci-fi classic: growing human babies outside the womb. Think the fetus fields from “The Matrix,” or the frozen embryos in “Alien: Covenant.”

In 1923, British biologist J.B.S. Haldane coined a term for that – ectogenesis. He predicted that 70% of pregnancies would take place, from fertilization to birth, in artificial wombs by 2074. That many seems unlikely, but the timeline is on track.

Developing an embryo outside the womb is already routine in in vitro fertilization. And technology enables preterm babies to survive through much of the second half of gestation. Normal human pregnancy is 40 weeks, and the youngest preterm baby ever to survive was 21 weeks and 1 day old, just a few days younger than a smattering of others who lived.

The biggest obstacle for babies younger than that is lung viability. Mechanical ventilation can damage the lungs and lead to a chronic (sometimes fatal) lung disease known as bronchopulmonary dysplasia. Avoiding this would mean figuring out a way to maintain fetal circulation – the intricate system that delivers oxygenated blood from the placenta to the fetus via the umbilical cord. Researchers at Children’s Hospital of Philadelphia have done this using a fetal lamb.

The key to their invention is a substitute placenta: an oxygenator connected to the lamb’s umbilical cord. Tubes inserted through the umbilical vein and arteries carry oxygenated blood from the “placenta” to the fetus, and deoxygenated blood back out. The lamb resides in an artificial, fluid-filled amniotic sac until its lungs and other organs are developed.

Fertility treatment could benefit, too. “An artificial womb may substitute in situations in which a gestational carrier – surrogate – is indicated,” says Paula Amato, MD, a professor of obstetrics and gynecology at Oregon Health and Science University, Portland. (Dr. Amato is not involved in the CHOP research.) For example: when the mother is missing a uterus or can’t carry a pregnancy safely.

No date is set for clinical trials yet. But according to the research, the main difference between human and lamb may come down to size. A lamb’s umbilical vessels are larger, so feeding in a tube is easier. With today’s advances in miniaturizing surgical methods, that seems like a challenge scientists can overcome.
 

Messenger RNA therapeutics

Back to “Star Trek.” The hypospray injector’s contents could cure just about any disease, even one newly discovered on a strange planet. That’s not unlike messenger RNA (mRNA) technology, a breakthrough that enabled scientists to quickly develop some of the first COVID-19 vaccines.

But vaccines are just the beginning of what this technology can do.

A whole field of immunotherapy is emerging that uses mRNA to deliver instructions to produce chimeric antigen receptor–modified immune cells (CAR-modified immune cells). These cells are engineered to target diseased cells and tissues, like cancer cells and harmful fibroblasts (scar tissue) that promote fibrosis in, for example, the heart and lungs.

The field is bursting with rodent research, and clinical trials have started for treating some advanced-stage malignancies.

Actual clinical use may be years away, but if all goes well, these medicines could help treat or even cure the core medical problems facing humanity. We’re talking cancer, heart disease, neurodegenerative disease – transforming one therapy into another by simply changing the mRNA’s “nucleotide sequence,” the blueprint containing instructions telling it what to do, and what disease to attack.

As this technology matures, we may start to feel as if we’re really on “Star Trek,” where Dr. Leonard “Bones” McCoy pulls out the same device to treat just about every disease or injury.

A version of this article first appeared on WebMD.com.

When I was a child, I watched syndicated episodes of the original “Star Trek.” I was dazzled by the space travel, sure, but also the medical technology.

A handheld “tricorder” detected diseases, while an intramuscular injector (“hypospray”) could treat them. Sickbay “biobeds” came with real-time health monitors that looked futuristic at the time but seem primitive today.

Such visions inspired a lot of us kids to pursue science. Little did we know the real-life advances many of us would see in our lifetimes.

Artificial intelligence helping to spot disease, robots performing surgery, even video calls between doctor and patient – all these once sounded fantastical but now happen in clinical care.

Now, in the 23rd year of the 21st century, you might not believe wht we’ll be capable of next. Three especially wild examples are moving closer to clinical reality. 
 

Human hibernation

Captain America, Han Solo, and “Star Trek” villain Khan – all were preserved at low temperatures and then revived, waking up alive and well months, decades, or centuries later. These are fictional examples, to be sure, but the science they’re rooted in is real.

Rare cases of accidental hypothermia prove that full recovery is possible even after the heart stops beating. The drop in body temperature slows metabolism and reduces the need for oxygen, stalling brain damage for an hour or more. (In one extreme case, a climber survived after almost 9 hours of efforts to revive him.)

Useful for a space traveler? Maybe not. But it’s potentially huge for someone with life-threatening injuries from a car accident or a gunshot wound.

That’s the thinking behind a breakthrough procedure that came after decades of research on pigs and dogs, now in a clinical trial. The idea: A person with massive blood loss whose heart has stopped is injected with an ice-cold fluid, cooling them from the inside, down to about 50° F.

Doctors already induce more modest hypothermia to protect the brain and other organs after cardiac arrest and during surgery on the aortic arch (the main artery carrying blood from the heart).

But this experimental procedure – called emergency preservation and resuscitation (EPR) – goes far beyond that, dramatically “decreasing the body’s need for oxygen and blood flow,” says Samuel Tisherman, MD, a trauma surgeon at the University of Maryland Medical Center and the trial’s lead researcher. This puts the patient in a state of suspended animation that “could buy time for surgeons to stop the bleeding and save more of these patients.”

The technique has been done on at least six patients, though none were reported to survive. The trial is expected to include 20 people by the time it wraps up in December, according to the listing on the U.S. clinical trials database. Though given the strict requirements for candidates (emergency trauma victims who are not likely to survive), one can’t exactly rely on a set schedule.

Still, the technology is promising. Someday we may even use it to keep patients in suspended animation for months or years, experts predict, helping astronauts through decades-long spaceflights, or stalling death in sick patients awaiting a cure.
 

Artificial womb

Another sci-fi classic: growing human babies outside the womb. Think the fetus fields from “The Matrix,” or the frozen embryos in “Alien: Covenant.”

In 1923, British biologist J.B.S. Haldane coined a term for that – ectogenesis. He predicted that 70% of pregnancies would take place, from fertilization to birth, in artificial wombs by 2074. That many seems unlikely, but the timeline is on track.

Developing an embryo outside the womb is already routine in in vitro fertilization. And technology enables preterm babies to survive through much of the second half of gestation. Normal human pregnancy is 40 weeks, and the youngest preterm baby ever to survive was 21 weeks and 1 day old, just a few days younger than a smattering of others who lived.

The biggest obstacle for babies younger than that is lung viability. Mechanical ventilation can damage the lungs and lead to a chronic (sometimes fatal) lung disease known as bronchopulmonary dysplasia. Avoiding this would mean figuring out a way to maintain fetal circulation – the intricate system that delivers oxygenated blood from the placenta to the fetus via the umbilical cord. Researchers at Children’s Hospital of Philadelphia have done this using a fetal lamb.

The key to their invention is a substitute placenta: an oxygenator connected to the lamb’s umbilical cord. Tubes inserted through the umbilical vein and arteries carry oxygenated blood from the “placenta” to the fetus, and deoxygenated blood back out. The lamb resides in an artificial, fluid-filled amniotic sac until its lungs and other organs are developed.

Fertility treatment could benefit, too. “An artificial womb may substitute in situations in which a gestational carrier – surrogate – is indicated,” says Paula Amato, MD, a professor of obstetrics and gynecology at Oregon Health and Science University, Portland. (Dr. Amato is not involved in the CHOP research.) For example: when the mother is missing a uterus or can’t carry a pregnancy safely.

No date is set for clinical trials yet. But according to the research, the main difference between human and lamb may come down to size. A lamb’s umbilical vessels are larger, so feeding in a tube is easier. With today’s advances in miniaturizing surgical methods, that seems like a challenge scientists can overcome.
 

Messenger RNA therapeutics

Back to “Star Trek.” The hypospray injector’s contents could cure just about any disease, even one newly discovered on a strange planet. That’s not unlike messenger RNA (mRNA) technology, a breakthrough that enabled scientists to quickly develop some of the first COVID-19 vaccines.

But vaccines are just the beginning of what this technology can do.

A whole field of immunotherapy is emerging that uses mRNA to deliver instructions to produce chimeric antigen receptor–modified immune cells (CAR-modified immune cells). These cells are engineered to target diseased cells and tissues, like cancer cells and harmful fibroblasts (scar tissue) that promote fibrosis in, for example, the heart and lungs.

The field is bursting with rodent research, and clinical trials have started for treating some advanced-stage malignancies.

Actual clinical use may be years away, but if all goes well, these medicines could help treat or even cure the core medical problems facing humanity. We’re talking cancer, heart disease, neurodegenerative disease – transforming one therapy into another by simply changing the mRNA’s “nucleotide sequence,” the blueprint containing instructions telling it what to do, and what disease to attack.

As this technology matures, we may start to feel as if we’re really on “Star Trek,” where Dr. Leonard “Bones” McCoy pulls out the same device to treat just about every disease or injury.

A version of this article first appeared on WebMD.com.

When I was a child, I watched syndicated episodes of the original “Star Trek.” I was dazzled by the space travel, sure, but also the medical technology.

A handheld “tricorder” detected diseases, while an intramuscular injector (“hypospray”) could treat them. Sickbay “biobeds” came with real-time health monitors that looked futuristic at the time but seem primitive today.

Such visions inspired a lot of us kids to pursue science. Little did we know the real-life advances many of us would see in our lifetimes.

Artificial intelligence helping to spot disease, robots performing surgery, even video calls between doctor and patient – all these once sounded fantastical but now happen in clinical care.

Now, in the 23rd year of the 21st century, you might not believe wht we’ll be capable of next. Three especially wild examples are moving closer to clinical reality. 
 

Human hibernation

Captain America, Han Solo, and “Star Trek” villain Khan – all were preserved at low temperatures and then revived, waking up alive and well months, decades, or centuries later. These are fictional examples, to be sure, but the science they’re rooted in is real.

Rare cases of accidental hypothermia prove that full recovery is possible even after the heart stops beating. The drop in body temperature slows metabolism and reduces the need for oxygen, stalling brain damage for an hour or more. (In one extreme case, a climber survived after almost 9 hours of efforts to revive him.)

Useful for a space traveler? Maybe not. But it’s potentially huge for someone with life-threatening injuries from a car accident or a gunshot wound.

That’s the thinking behind a breakthrough procedure that came after decades of research on pigs and dogs, now in a clinical trial. The idea: A person with massive blood loss whose heart has stopped is injected with an ice-cold fluid, cooling them from the inside, down to about 50° F.

Doctors already induce more modest hypothermia to protect the brain and other organs after cardiac arrest and during surgery on the aortic arch (the main artery carrying blood from the heart).

But this experimental procedure – called emergency preservation and resuscitation (EPR) – goes far beyond that, dramatically “decreasing the body’s need for oxygen and blood flow,” says Samuel Tisherman, MD, a trauma surgeon at the University of Maryland Medical Center and the trial’s lead researcher. This puts the patient in a state of suspended animation that “could buy time for surgeons to stop the bleeding and save more of these patients.”

The technique has been done on at least six patients, though none were reported to survive. The trial is expected to include 20 people by the time it wraps up in December, according to the listing on the U.S. clinical trials database. Though given the strict requirements for candidates (emergency trauma victims who are not likely to survive), one can’t exactly rely on a set schedule.

Still, the technology is promising. Someday we may even use it to keep patients in suspended animation for months or years, experts predict, helping astronauts through decades-long spaceflights, or stalling death in sick patients awaiting a cure.
 

Artificial womb

Another sci-fi classic: growing human babies outside the womb. Think the fetus fields from “The Matrix,” or the frozen embryos in “Alien: Covenant.”

In 1923, British biologist J.B.S. Haldane coined a term for that – ectogenesis. He predicted that 70% of pregnancies would take place, from fertilization to birth, in artificial wombs by 2074. That many seems unlikely, but the timeline is on track.

Developing an embryo outside the womb is already routine in in vitro fertilization. And technology enables preterm babies to survive through much of the second half of gestation. Normal human pregnancy is 40 weeks, and the youngest preterm baby ever to survive was 21 weeks and 1 day old, just a few days younger than a smattering of others who lived.

The biggest obstacle for babies younger than that is lung viability. Mechanical ventilation can damage the lungs and lead to a chronic (sometimes fatal) lung disease known as bronchopulmonary dysplasia. Avoiding this would mean figuring out a way to maintain fetal circulation – the intricate system that delivers oxygenated blood from the placenta to the fetus via the umbilical cord. Researchers at Children’s Hospital of Philadelphia have done this using a fetal lamb.

The key to their invention is a substitute placenta: an oxygenator connected to the lamb’s umbilical cord. Tubes inserted through the umbilical vein and arteries carry oxygenated blood from the “placenta” to the fetus, and deoxygenated blood back out. The lamb resides in an artificial, fluid-filled amniotic sac until its lungs and other organs are developed.

Fertility treatment could benefit, too. “An artificial womb may substitute in situations in which a gestational carrier – surrogate – is indicated,” says Paula Amato, MD, a professor of obstetrics and gynecology at Oregon Health and Science University, Portland. (Dr. Amato is not involved in the CHOP research.) For example: when the mother is missing a uterus or can’t carry a pregnancy safely.

No date is set for clinical trials yet. But according to the research, the main difference between human and lamb may come down to size. A lamb’s umbilical vessels are larger, so feeding in a tube is easier. With today’s advances in miniaturizing surgical methods, that seems like a challenge scientists can overcome.
 

Messenger RNA therapeutics

Back to “Star Trek.” The hypospray injector’s contents could cure just about any disease, even one newly discovered on a strange planet. That’s not unlike messenger RNA (mRNA) technology, a breakthrough that enabled scientists to quickly develop some of the first COVID-19 vaccines.

But vaccines are just the beginning of what this technology can do.

A whole field of immunotherapy is emerging that uses mRNA to deliver instructions to produce chimeric antigen receptor–modified immune cells (CAR-modified immune cells). These cells are engineered to target diseased cells and tissues, like cancer cells and harmful fibroblasts (scar tissue) that promote fibrosis in, for example, the heart and lungs.

The field is bursting with rodent research, and clinical trials have started for treating some advanced-stage malignancies.

Actual clinical use may be years away, but if all goes well, these medicines could help treat or even cure the core medical problems facing humanity. We’re talking cancer, heart disease, neurodegenerative disease – transforming one therapy into another by simply changing the mRNA’s “nucleotide sequence,” the blueprint containing instructions telling it what to do, and what disease to attack.

As this technology matures, we may start to feel as if we’re really on “Star Trek,” where Dr. Leonard “Bones” McCoy pulls out the same device to treat just about every disease or injury.

A version of this article first appeared on WebMD.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.
 

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.
 

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.
 

Brain indicators of motor impairment were distinct among children with autism spectrum disorder (ASD), those with developmental coordination disorder (DCD), and controls, in a new study.

Previous research suggests that individuals with ASD overlap in motor impairment with those with DCD. But these two conditions may differ significantly in some areas, as children with ASD tend to show weaker skills in social motor tasks such as imitation, wrote Emil Kilroy, PhD, of the University of Southern California, Los Angeles, and colleagues.

The neurobiological basis of autism remains unknown, despite many research efforts, in part because of the heterogeneity of the disease, said corresponding author Lisa Aziz-Zadeh, PhD, also of the University of Southern California, in an interview.

Comorbidity with other disorders is a strong contributing factor to heterogeneity, and approximately 80% of autistic individuals have motor impairments and meet criteria for a diagnosis of DCD, said Dr. Aziz-Zadeh. “Controlling for other comorbidities, such as developmental coordination disorder, when trying to understand the neural basis of autism is important, so that we can understand which neural circuits are related to [core symptoms of autism] and which ones are related to motor impairments that are comorbid with autism, but not necessarily part of the core symptomology,” she explained. “We focused on white matter pathways here because many researchers now think the underlying basis of autism, besides genetics, is brain connectivity differences.”

In their study published in Scientific Reports, the researchers reviewed data from whole-brain correlational tractography for 22 individuals with autism spectrum disorder, 16 with developmental coordination disorder, and 21 normally developing individuals, who served as the control group. The mean age of the participants was approximately 11 years; the age range was 8-17 years.

Overall, patterns of brain diffusion (movement of fluid, mainly water molecules, in the brain) were significantly different in ASD children, compared with typically developing children.

The ASD group showed significantly reduced diffusivity in the bilateral fronto-parietal cingulum and the left parolfactory cingulum. This finding reflects previous studies suggesting an association between brain patterns in the cingulum area and ASD. But the current study is “the first to identify the fronto-parietal and the parolfactory portions of the cingulum as well as the anterior caudal u-fibers as specific to core ASD symptomatology and not related to motor-related comorbidity,” the researchers wrote.

Differences in brain diffusivity were associated with worse performance on motor skills and behavioral measures for children with ASD and children with DCD, compared with controls.

Motor development was assessed using the Total Movement Assessment Battery for Children-2 (MABC-2) and the Florida Apraxia Battery modified for children (FAB-M). The MABC-2 is among the most common tools for measuring motor skills and identifying clinically relevant motor deficits in children and teens aged 3-16 years. The test includes three subtest scores (manual dexterity, gross-motor aiming and catching, and balance) and a total score. Scores are based on a child’s best performance on each component, and higher scores indicate better functioning. In the new study, The MABC-2 total scores averaged 10.57 for controls, compared with 5.76 in the ASD group, and 4.31 in the DCD group.

Children with ASD differed from the other groups in social measures. Social skills were measured using several tools, including the Social Responsivity Scale (SRS Total), which is a parent-completed survey that includes a total score designed to reflect the severity of social deficits in ASD. It is divided into five subscales for parents to assess a child’s social skill impairment: social awareness, social cognition, social communication, social motivation, and mannerisms. Scores for the SRS are calculated in T-scores, in which a score of 50 represents the mean. T-scores of 59 and below are generally not associated with ASD, and patients with these scores are considered to have low to no symptomatology. Scores on the SRS Total in the new study were 45.95, 77.45, and 55.81 for the controls, ASD group, and DCD group, respectively.
 

Results should raise awareness

“The results were largely predicted in our hypotheses – that we would find specific white matter pathways in autism that would differ from [what we saw in typically developing patients and those with DCD], and that diffusivity in ASD would be related to socioemotional differences,” Dr. Aziz-Zadeh said, in an interview.

“What was surprising was that some pathways that had previously been thought to be different in autism were also compromised in DCD, indicating that they were common to motor deficits which both groups shared, not to core autism symptomology,” she noted.

A message for clinicians from the study is that a dual diagnosis of DCD is often missing in ASD practice, said Dr. Aziz-Zadeh. “Given that approximately 80% of children with ASD have DCD, testing for DCD and addressing potential motor issues should be more common practice,” she said.

Dr. Aziz-Zadeh and colleagues are now investigating relationships between the brain, behavior, and the gut microbiome. “We think that understanding autism from a full-body perspective, examining interactions between the brain and the body, will be an important step in this field,” she emphasized.

The study was limited by several factors, including the small sample size, the use of only right-handed participants, and the use of self-reports by children and parents, the researchers noted. Additionally, they noted that white matter develops at different rates in different age groups, and future studies might consider age as a factor, as well as further behavioral assessments, they said.
 

Small sample size limits conclusions

“Understanding the neuroanatomic differences that may contribute to the core symptoms of ASD is a very important goal for the field, particularly how they relate to other comorbid symptoms and neurodevelopmental disorders,” said Michael Gandal, MD, of the department of psychiatry at the University of Pennsylvania, Philadelphia, and a member of the Lifespan Brain Institute at the Children’s Hospital of Philadelphia, in an interview.

“While this study provides some clues into how structural connectivity may relate to motor coordination in ASD, it will be important to replicate these findings in a much larger sample before we can really appreciate how robust these findings are and how well they generalize to the broader ASD population,” Dr. Gandal emphasized.

The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The researchers had no financial conflicts to disclose. Dr. Gandal had no financial conflicts to disclose.

Brain indicators of motor impairment were distinct among children with autism spectrum disorder (ASD), those with developmental coordination disorder (DCD), and controls, in a new study.

Previous research suggests that individuals with ASD overlap in motor impairment with those with DCD. But these two conditions may differ significantly in some areas, as children with ASD tend to show weaker skills in social motor tasks such as imitation, wrote Emil Kilroy, PhD, of the University of Southern California, Los Angeles, and colleagues.

The neurobiological basis of autism remains unknown, despite many research efforts, in part because of the heterogeneity of the disease, said corresponding author Lisa Aziz-Zadeh, PhD, also of the University of Southern California, in an interview.

Comorbidity with other disorders is a strong contributing factor to heterogeneity, and approximately 80% of autistic individuals have motor impairments and meet criteria for a diagnosis of DCD, said Dr. Aziz-Zadeh. “Controlling for other comorbidities, such as developmental coordination disorder, when trying to understand the neural basis of autism is important, so that we can understand which neural circuits are related to [core symptoms of autism] and which ones are related to motor impairments that are comorbid with autism, but not necessarily part of the core symptomology,” she explained. “We focused on white matter pathways here because many researchers now think the underlying basis of autism, besides genetics, is brain connectivity differences.”

In their study published in Scientific Reports, the researchers reviewed data from whole-brain correlational tractography for 22 individuals with autism spectrum disorder, 16 with developmental coordination disorder, and 21 normally developing individuals, who served as the control group. The mean age of the participants was approximately 11 years; the age range was 8-17 years.

Overall, patterns of brain diffusion (movement of fluid, mainly water molecules, in the brain) were significantly different in ASD children, compared with typically developing children.

The ASD group showed significantly reduced diffusivity in the bilateral fronto-parietal cingulum and the left parolfactory cingulum. This finding reflects previous studies suggesting an association between brain patterns in the cingulum area and ASD. But the current study is “the first to identify the fronto-parietal and the parolfactory portions of the cingulum as well as the anterior caudal u-fibers as specific to core ASD symptomatology and not related to motor-related comorbidity,” the researchers wrote.

Differences in brain diffusivity were associated with worse performance on motor skills and behavioral measures for children with ASD and children with DCD, compared with controls.

Motor development was assessed using the Total Movement Assessment Battery for Children-2 (MABC-2) and the Florida Apraxia Battery modified for children (FAB-M). The MABC-2 is among the most common tools for measuring motor skills and identifying clinically relevant motor deficits in children and teens aged 3-16 years. The test includes three subtest scores (manual dexterity, gross-motor aiming and catching, and balance) and a total score. Scores are based on a child’s best performance on each component, and higher scores indicate better functioning. In the new study, The MABC-2 total scores averaged 10.57 for controls, compared with 5.76 in the ASD group, and 4.31 in the DCD group.

Children with ASD differed from the other groups in social measures. Social skills were measured using several tools, including the Social Responsivity Scale (SRS Total), which is a parent-completed survey that includes a total score designed to reflect the severity of social deficits in ASD. It is divided into five subscales for parents to assess a child’s social skill impairment: social awareness, social cognition, social communication, social motivation, and mannerisms. Scores for the SRS are calculated in T-scores, in which a score of 50 represents the mean. T-scores of 59 and below are generally not associated with ASD, and patients with these scores are considered to have low to no symptomatology. Scores on the SRS Total in the new study were 45.95, 77.45, and 55.81 for the controls, ASD group, and DCD group, respectively.
 

Results should raise awareness

“The results were largely predicted in our hypotheses – that we would find specific white matter pathways in autism that would differ from [what we saw in typically developing patients and those with DCD], and that diffusivity in ASD would be related to socioemotional differences,” Dr. Aziz-Zadeh said, in an interview.

“What was surprising was that some pathways that had previously been thought to be different in autism were also compromised in DCD, indicating that they were common to motor deficits which both groups shared, not to core autism symptomology,” she noted.

A message for clinicians from the study is that a dual diagnosis of DCD is often missing in ASD practice, said Dr. Aziz-Zadeh. “Given that approximately 80% of children with ASD have DCD, testing for DCD and addressing potential motor issues should be more common practice,” she said.

Dr. Aziz-Zadeh and colleagues are now investigating relationships between the brain, behavior, and the gut microbiome. “We think that understanding autism from a full-body perspective, examining interactions between the brain and the body, will be an important step in this field,” she emphasized.

The study was limited by several factors, including the small sample size, the use of only right-handed participants, and the use of self-reports by children and parents, the researchers noted. Additionally, they noted that white matter develops at different rates in different age groups, and future studies might consider age as a factor, as well as further behavioral assessments, they said.
 

Small sample size limits conclusions

“Understanding the neuroanatomic differences that may contribute to the core symptoms of ASD is a very important goal for the field, particularly how they relate to other comorbid symptoms and neurodevelopmental disorders,” said Michael Gandal, MD, of the department of psychiatry at the University of Pennsylvania, Philadelphia, and a member of the Lifespan Brain Institute at the Children’s Hospital of Philadelphia, in an interview.

“While this study provides some clues into how structural connectivity may relate to motor coordination in ASD, it will be important to replicate these findings in a much larger sample before we can really appreciate how robust these findings are and how well they generalize to the broader ASD population,” Dr. Gandal emphasized.

The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The researchers had no financial conflicts to disclose. Dr. Gandal had no financial conflicts to disclose.

Brain indicators of motor impairment were distinct among children with autism spectrum disorder (ASD), those with developmental coordination disorder (DCD), and controls, in a new study.

Previous research suggests that individuals with ASD overlap in motor impairment with those with DCD. But these two conditions may differ significantly in some areas, as children with ASD tend to show weaker skills in social motor tasks such as imitation, wrote Emil Kilroy, PhD, of the University of Southern California, Los Angeles, and colleagues.

The neurobiological basis of autism remains unknown, despite many research efforts, in part because of the heterogeneity of the disease, said corresponding author Lisa Aziz-Zadeh, PhD, also of the University of Southern California, in an interview.

Comorbidity with other disorders is a strong contributing factor to heterogeneity, and approximately 80% of autistic individuals have motor impairments and meet criteria for a diagnosis of DCD, said Dr. Aziz-Zadeh. “Controlling for other comorbidities, such as developmental coordination disorder, when trying to understand the neural basis of autism is important, so that we can understand which neural circuits are related to [core symptoms of autism] and which ones are related to motor impairments that are comorbid with autism, but not necessarily part of the core symptomology,” she explained. “We focused on white matter pathways here because many researchers now think the underlying basis of autism, besides genetics, is brain connectivity differences.”

In their study published in Scientific Reports, the researchers reviewed data from whole-brain correlational tractography for 22 individuals with autism spectrum disorder, 16 with developmental coordination disorder, and 21 normally developing individuals, who served as the control group. The mean age of the participants was approximately 11 years; the age range was 8-17 years.

Overall, patterns of brain diffusion (movement of fluid, mainly water molecules, in the brain) were significantly different in ASD children, compared with typically developing children.

The ASD group showed significantly reduced diffusivity in the bilateral fronto-parietal cingulum and the left parolfactory cingulum. This finding reflects previous studies suggesting an association between brain patterns in the cingulum area and ASD. But the current study is “the first to identify the fronto-parietal and the parolfactory portions of the cingulum as well as the anterior caudal u-fibers as specific to core ASD symptomatology and not related to motor-related comorbidity,” the researchers wrote.

Differences in brain diffusivity were associated with worse performance on motor skills and behavioral measures for children with ASD and children with DCD, compared with controls.

Motor development was assessed using the Total Movement Assessment Battery for Children-2 (MABC-2) and the Florida Apraxia Battery modified for children (FAB-M). The MABC-2 is among the most common tools for measuring motor skills and identifying clinically relevant motor deficits in children and teens aged 3-16 years. The test includes three subtest scores (manual dexterity, gross-motor aiming and catching, and balance) and a total score. Scores are based on a child’s best performance on each component, and higher scores indicate better functioning. In the new study, The MABC-2 total scores averaged 10.57 for controls, compared with 5.76 in the ASD group, and 4.31 in the DCD group.

Children with ASD differed from the other groups in social measures. Social skills were measured using several tools, including the Social Responsivity Scale (SRS Total), which is a parent-completed survey that includes a total score designed to reflect the severity of social deficits in ASD. It is divided into five subscales for parents to assess a child’s social skill impairment: social awareness, social cognition, social communication, social motivation, and mannerisms. Scores for the SRS are calculated in T-scores, in which a score of 50 represents the mean. T-scores of 59 and below are generally not associated with ASD, and patients with these scores are considered to have low to no symptomatology. Scores on the SRS Total in the new study were 45.95, 77.45, and 55.81 for the controls, ASD group, and DCD group, respectively.
 

Results should raise awareness

“The results were largely predicted in our hypotheses – that we would find specific white matter pathways in autism that would differ from [what we saw in typically developing patients and those with DCD], and that diffusivity in ASD would be related to socioemotional differences,” Dr. Aziz-Zadeh said, in an interview.

“What was surprising was that some pathways that had previously been thought to be different in autism were also compromised in DCD, indicating that they were common to motor deficits which both groups shared, not to core autism symptomology,” she noted.

A message for clinicians from the study is that a dual diagnosis of DCD is often missing in ASD practice, said Dr. Aziz-Zadeh. “Given that approximately 80% of children with ASD have DCD, testing for DCD and addressing potential motor issues should be more common practice,” she said.

Dr. Aziz-Zadeh and colleagues are now investigating relationships between the brain, behavior, and the gut microbiome. “We think that understanding autism from a full-body perspective, examining interactions between the brain and the body, will be an important step in this field,” she emphasized.

The study was limited by several factors, including the small sample size, the use of only right-handed participants, and the use of self-reports by children and parents, the researchers noted. Additionally, they noted that white matter develops at different rates in different age groups, and future studies might consider age as a factor, as well as further behavioral assessments, they said.
 

Small sample size limits conclusions

“Understanding the neuroanatomic differences that may contribute to the core symptoms of ASD is a very important goal for the field, particularly how they relate to other comorbid symptoms and neurodevelopmental disorders,” said Michael Gandal, MD, of the department of psychiatry at the University of Pennsylvania, Philadelphia, and a member of the Lifespan Brain Institute at the Children’s Hospital of Philadelphia, in an interview.

“While this study provides some clues into how structural connectivity may relate to motor coordination in ASD, it will be important to replicate these findings in a much larger sample before we can really appreciate how robust these findings are and how well they generalize to the broader ASD population,” Dr. Gandal emphasized.

The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The researchers had no financial conflicts to disclose. Dr. Gandal had no financial conflicts to disclose.

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

Neuromuscular diseases (NMDs) are a broad classification of heterogeneous groups of disorders characterized by progressive muscle weakness resulting from muscle or nerve dysfunction.¹ Diagnosis is based on symptoms and a full medical history, as well as on muscle and imaging tests (including electromyography, nerve-conduction studies, magnetic resonance imaging, muscle biopsy, and blood tests) to confirm or rule out specific NMDs.² Early diagnosis of NMDs can be difficult because symptoms overlap with those of many other diseases.

Although individually, NMDs are rare, collectively, they affect approximately 250,000 people in the United States. Disease types vary in regard to cause, symptoms, prevalence, age of onset, progression, and severity. Functional impairment from any NMD can lead to lifelong morbidities and shortened life expectancy.^1,3

Treatment options for NMDs are limited; most target symptoms, not disease progression. Although there is a need for safe and effective gene-based therapies for NMDs, there are challenges to developing and delivering such treatments that have impeded clinical success. These include a lack of understanding about disease pathology and drug targets, limited animal model systems, and few reliable biomarkers that are predictive of therapeutic success.^4,5

Amyotrophic lateral sclerosis

ALS is caused by progressive degeneration of upper- and lower-motor neurons, which eventually leads to respiratory failure and death 3 to 5 years after disease onset.^7-9 There are two subtypes: Familial ALS (10% of cases) and sporadic ALS (90% of cases). Commonly mutated ALS-associated genes^6,8 are:

• Superoxide dismutase type 1 (SOD1).
• Chromosome 9 open reading frame 72 (C9orf72).
• Transactive response DNA-binding protein 43 (TARDBP).
• Fused in sarcoma (FUS).

SOD1-targeted therapy is being studied, with early evidence of clinical success. Mutations in SOD1 account for 10% to 20% of familial ALS cases and 1% to 2% of sporadic ALS cases.^6,10 10 Mutations in C9orf72 account for 25 to 40% of familial ALS cases and 7% of sporadic ALS cases.^8,9,11 Mutations in TARDBP account for 3% of familial ALS cases and 2% of sporadic cases.¹² Mutations in FUS account for 4% of familial ALS cases and 1% of sporadic cases. Overall, these mutant proteins can trigger neurotoxicity, thus inducing motor-neuron death.^6,10
 

Treatment of ALS

Two treatments for ALS are Food and Drug Administration approved: riluzole (Rilutek), approved in 1995, and edaravone (Radicava), approved in 2017.

Riluzole is an oral anti-excitotoxic glutamate antagonist.¹¹ Approval of riluzole was based on the results of two studies that demonstrated a 2- to 3-month survival benefit.^10,14 For patients who have difficulty swallowing, an oral suspension (Tiglutik, approved in 2018) and an oral film (Exservan, approved in 2019) are available.

Edaravone is a free-radical scavenger that decreases oxidative stress and is administered intravenously (IV).^9,13,14 Findings from clinical trials suggest functional improvement or slower decline in function for some patients.

Although these two agents demonstrate modest therapeutic benefit, neither reverses progression of disease.^10,14
 

Gene-based therapy for ALS

Many non-viral strategies, including antisense oligonucleotide (ASO), monoclonal antibodies, reverse transcriptase inhibitors, and HGF gene replacement therapy are used as therapeutic approaches to SOD1, C9orf72, and FUS gene mutations in ALS patients, and are being evaluated in clinical studies^14,15 (Table 1^13-17).

• Change from baseline in CSF SOD1 protein concentration.¹⁷ Percent reduction in the total SOD1 protein level was much higher in the tofersen-treated group than in the control group (38% more than controls in the faster-progressing population; 26% more than controls in the slower-progressing population).¹⁸
• Change from baseline in neurofilament light-chain concentration in plasma.^17,18 Percent reduction in the level of neurofilament light chain was also observed to be higher in the tofersen-treated group than in the control group (67% more than controls in the faster-progressing population and 48% more than controls in the slower-progressing population).¹⁸

Because of these encouraging results, VALOR participants were moved to the ongoing open-label extension trial of tofersen (ClinicalTri-als.gov Identifier: NCT03070119), in which both groups were treated with the active agent.

These data suggest that early tofersen treatment might slow decline in faster-progressing patients and stabilize clinical function in slower-progressing patients.^18,19 Overall, most adverse events (AEs) in the trial among patients receiving active treatment were of mild or moderate severity, and were largely consistent with either disease progression or lumbar puncture–related complications.¹⁸

Because data from VALOR suggested potential benefit from tofersen, the ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) is investigating the clinical value of presymptomatic treatment and the optimal timing of initiation of therapy.^20,21 ATLAS is a phase 3, randomized, placebo-controlled trial that examines the clinical efficacy, safety, and tolerability of tofersen in presymptomatic adult carriers of SOD1 mutation who have an elevated neurofilament light-chain concentration.²¹ ATLAS will also evaluate the efficacy of tofersen when initiated before, rather than after, ALS manifests clinically. Enrollment is still open for this trial.^20,21

Latozinemab, also known as AL001, is a first-in-class monoclonal antibody, administered by IV infusion, that elevates levels of progranulin, a key regulator of the immune activity and lysosomal function in the brain.^22,23 Latozinemab limits progranulin endocytosis and degradation by sortilin inhibition.²² Progranulin gene mutations can reduce progranulin expression (by 50 to 70 percent reduction), which may cause neuro-degeneration due to abnormal accumulation of TAR-DNA-binding protein 43 (TDP-43) in the brain cells.^22,24 TDP-43 pathology has also been shown to be associated with C9orf72 mutations.²³ Although the mechanism is not fully understood, the role of progranulin deficiency in TDP-43 pathology is believed to be associated with neurodegenerative diseases like ALS.11,23,24,43 Previous animal models of chronic neurodegenera-tion have demonstrated how increased progranulin levels can be protective against TDP-43 pathology, increasing neuronal development and survival, thus potentially slowing disease progression.^23,24,43 Currently, latozinemab is being investigated in a randomized, double-blind, placebo-controlled, multicenter phase 2 trial (ClinicalTrials.gov Identifier: NCT05053035). Approximately, 45 C90rf72-associated ALS participants (≥ 18 years of age) will receive latozinemab or placebo infusions every 4 weeks (for 24 weeks). Study endpoints include safety, tolerability, PK, PD, as well as plasma, and CSF progranulin levels.²⁵ In previous studies, latozinemab demonstrated encouraging results in frontotemporal dementia (FTD) patients who carry a progranulin mutation. Because FTD was revealed to have significant genetic overlap with ALS, there is disease-modifying potential for latozinemab in ALS patients.^23,24

TPN-101 is a nucleoside analog reverse transcriptase inhibitor, administered orally, that was originally developed for human immunodeficiency virus (HIV) treatment. However, due to recent findings suggesting retrotransposon activity contributing to neurodegeneration in TDP-43 mediated diseases, including ALS and FTD, TNP-101 is being repurposed.²⁶ The safety and tolerability of TNP-101 are currently being evaluated in C9orf72-associated ALS and FTD patients (≥ 18 years of age). The study is a randomized, double-blind, placebo-controlled paral-lel-group phase 2a trial (ClinicalTrials.gov Identifier: NCT04993755) The study includes a screening period of 6 weeks, double-blind treatment period of 24 weeks, an open-label treatment period of 24 weeks, and 4 weeks of the post-treatment follow-up visit. Study endpoints include the incidence and severity of spontaneously reported treatment-emergent adverse events (TEAEs) associated with TNP-101 and placebo for a to-tal of 48 weeks.²⁷

ION363 is an investigational ASO, administered by IT injection, that selectively targets one of the FUS mutations (p.P525L), which is responsible for earlier disease onset and rapid ALS progression.^28,29 The clinical efficacy of ION363, specifically in clinical function and survival is being assessed in FUS-associated ALS patients (≥ 12 years of age). This randomized phase 3 study (ClinicalTrials.gov Identifier: NCT04768972) includes two parts; part 1 will consist of participants receiving a multi-dose regimen (1 dose every 4-12 weeks) of ION363 or placebo for 61 weeks followed by an open-label extension treatment period in part 2, which will consist of participants receiving ION363 (every 12 weeks) for 85 weeks. The primary endpoint of the study is the change from baseline to day 505 in functional impairment, using ALS Functional Rating Scale-Revised (ALSFRS-R). This measures functional disease severity, specifically in bulbar function, gross motor skills, fine motor skills, and respiratory. The score for all 12 questions can range from 0 (no function) to 4 (full function) with a total possible score of 48.³⁰

Engensis, also known as VM202, is a non-viral gene therapy, administered by intramuscular (IM) injection, that uses a plasmid to deliver the hepatocyte growth factor (HGF) gene to promote HGF protein production. The HGF protein plays a role in angiogenesis, the previous of muscle atrophy, and the promotion of neuronal survival and growth. Based on preclinical studies, increasing HGF protein production has been shown to reduce neurodegeneration, thus potentially halting or slowing ALS progression.³¹ Currently, the safety of engensis is being evaluated in ALS patients (18-80 years of age) in the REViVALS phase 2a (ClinicalTrials.gov Identifier: NCT04632225)/2b (ClinicalTrial.gov Identifier: NCT05176093).^32,33 The ReViVALS trial is a double-blind, randomized, placebo-controlled, multi-center study. The phase 2a study endpoints include the incidence of TEAEs, treatment-emergent serious adverse events (TESAEs), injection site reactions, and clinically significant labor-atory values post-treatment (engensis vs placebo group) for 180 days.³³ A phase 2b study will evaluate the long-term safety of engensis for an additional 6 months. Study endpoints include the incidence of AEs, changes from baseline in ALSFRS-R scores to evaluate improvement in muscle function, changes from baseline in quality of life using the ALS patient assessment questionnaire, time to all-cause mortality compared to placebo, etc.³²
 

Spinal muscular atrophy

SMA is a hereditary lower motor-neuron disease caused (in 95% of cases) by deletions or, less commonly, by mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5q13 that encodes the SMN protein.⁶ Reduction in expression of the SMN protein causes motor neurons to degenerate.^36-38 Because of a large inverted duplication in chromosome 5q, two variants of SMN (SMN1 and SMN2) exist on each allele. The paralog gene, SMN2, also produces the SMN protein – although at a lower level (10% to 20% of total SMN protein production) than SMN1 does.

A single nucleotide substitution in SMN2 alters splicing and suppresses transcription of exon 7, resulting in a shortened mRNA strand that yields a truncated SMN protein product.^6,37,39 SMA is classified based on age of onset and maximum motor abilities achieved, ranging from the most severe (Type 0) to mildest (Type 4) disease.^36,40 Because SMA patients lack functional SMN1 (due to polymorphisms), disease severity is determined by copy numbers of SMN2.^6,39

 

Gene-based therapy for SMA

Three FDA-approved SMN treatments demonstrate clinically meaningful benefit in SMA: SMN2-targeting nusinersen [Spinraza] and risdiplam [Evrysdi], and SMN1-targeting onasemnogene abeparvovec-xioi [Zolgensma]³⁸ Additional approaches to SMA treatment are through SMN-independent therapies, which target muscle and nerve function. Research has strongly suggested that combined SMA therapies, specifically approved SMN-targeted and investigational SMN-independent treatments, such as GYM329 (also known as RO7204239) may be the best strategy to treat all ages, stages, and types of SMA.⁴¹ (Table 2^26-41).

• Percentage of motor milestones responders, as determined using Section 2 of the Hammersmith Infant Neurological Examination–Part 2.
• Event-free survival (that is, avoidance of combined endpoint of death or permanent ventilation).

ENDEAR met the first primary efficacy outcome, demonstrating statistically significant (P < .0001) improvement in motor milestones (head control, rolling, independent sitting, and standing). By 13 months of age, approximately 51% of nusinersen-treated participants showed improvement, compared with none in the control group.^46,47

The second primary endpoint was also met, with a statistically significant (P = .005) 47% decrease in mortality or permanent ventilation use.^46-48

The NURTURE (ClinicalTrial.gov Identifier: NCT02386553) study is also investigating the efficacy and safety of nusinersen. An ongoing, open-label, supportive phase 2 trial, NURTURE is evaluating the efficacy and safety of multiple doses of nusinersen in 25 presymptomatic SMA patients (≤ 6 weeks of age). The primary endpoint of this study is time to death or respiratory intervention.⁴⁹ Interim results demonstrate that 100% of presymptomatic infants are functioning without respiratory intervention after median follow-up of 2.9 years.^46-48

Although nusinersen has been shown to be generally safe in clinical studies, development of lumbar puncture–related complications, as well as the need for sedation during IT administration, might affect treatment tolerability in some patients.³⁹

Risdiplam was approved by the FDA in 2020 as the first orally administered small-molecule treatment of SMA (for patients ≤ 2 months of age).⁵² Risdiplam is a SMN2 splicing modifier, binding to the 5’ splice site of intron 7 and exonic splicing enhancer 2 in exon 7 of SMN2 pre-mRNA. This alternative splicing increases efficiency in SMN2 gene transcription, thus increasing SMN protein production in motor-neuron cells.³⁶ An important advantage of risdiplam is the convenience of oral administration: A large percentage of SMA patients (that is, those with Type 2 disease) have severe scoliosis, which can further complicate therapy or deter patients from using a treatment that is administered through the IT route.⁴⁰

FDA approval of risdiplam was based on clinical data from two pivotal studies, FIREFISH (ClinicalTrial.gov Identifier: NCT02913482) and SUNFISH (ClinicalTrial.gov Identifier: NCT02908685).^53-54

FIREFISH is an open-label, phase 2/3 ongoing trial in infants (1-7 months of age) with SMA Type 1. The study comprises two parts; Part 1 determined the dose of risdiplam used in Part 2, which assessed the efficacy and safety of risdiplam for 24 months. The primary endpoint was the percentage of infants sitting without support for 5 seconds after 12 months of treatment using the gross motor scale of the Bayley Scales of Infant and Toddler Development–Third Edition. A statistically significant (P < .0001) therapeutic benefit was observed in motor milestones. Approximately 29% of infants achieved the motor milestone of independent sitting for 5 seconds, which had not been observed in the natural history of SMA.^53-55

SUNFISH is an ongoing randomized, double-blind, placebo-controlled trial of risdiplam in adult and pediatric patients with SMA Types 2 and 3 (2-25 years old). This phase 2/3 study comprises two parts: Part 1 determined the dose (for 12 weeks) to be used for confirmatory Part 2 (for 12 to 24 months). The primary endpoint was the change from baseline on the 32-item Motor Function Measure at 12 months. The study met its primary endpoint, demonstrating statistically significant (P = .0156) improvement in motor function scores, with a 1.36-point increase in the risdiplam group, compared with a 0.19-point decrease in the control group.^54,55

Ongoing risdiplam clinical trials also include JEWELFISH (ClinicalTrial.gov Identifier: NCT03032172) and RAINBOW (ClinicalTrial.gov Identifier: NCT03779334).^56-57 JEWELFISH is an open-label, phase 2 trial assessing the safety of risdiplam in patients (6 months to 60 years old) who received prior treatment. The study has completed recruitment; results are pending.⁵⁶ RAINBOW is an ongoing, open-label, single-arm, phase 2 trial, evaluating the clinical efficacy and safety of risdiplam in SMA-presymptomatic newborns (≤ 6 weeks old). The study is open for enrollment.⁵⁷ Overall, interim results for JEWELFISH and RAINBOW appear promising.

In addition, combined SMA therapies, specifically risdiplam and GYM329 are currently being investigated to address the underlying cause and symptoms of SMA concurrently.⁵⁸ GYM329, is an investigational anti-myostatin antibody, selectively binding preforms of myostatin - pro-myostatin and latent myostatin, thus improving muscle mass and strength for SMA patients.⁵⁹ The safety and efficacy of GYM329 in combination with risdiplam is currently being investigated in 180 ambulant participants with SMA (2-10 years of age) in the MANATEE (ClinicalTrial.gov Identifier: NCT05115110) phase 2/3 trial. The MANATEE study is a two-part, seamless, randomized, placebo-controlled, double-blind trial. Part 1 will assess the safety of the combination treatment in approximately 36 participants; participants will receive both GYM329 (every 4 weeks) by subcutaneous (SC) injection into the abdomen and risdiplam (once per day) for 24 weeks followed by a 72-week open-label treatment period. ^54,58 The outcome measures include the incidence of AEs, percentage change from baseline in the contractile area of skeletal muscle (in dominant thigh and calf), change from baseline in RHS total score, and incidence of change from baseline in serum concentration (total myostatin, free latent myostatin, and mature myostatin) etc.⁵⁴ Part 2 will be conducted on 144 participants, specifically assessing the efficacy and safety of the optimal dose of GYM329 selected from Part 1 (combined with risdiplam) for 72 weeks. Once the treatment period is completed in either part, participants can partake in a 2-year open-label extension period.^54,58 Other outcome measures include change from baseline in lean muscle mass (assessed by full body dual-energy X- ray absorptiometry (DXA) scan), in time taken to walk/run 10 meters (measured by RHS), in time taken to rise from the floor (measured by RHS), etc.⁵⁴ Overall, this combination treatment has the potential to further improve SMA patient outcomes and will be further investigated in other patient populations (including non-ambulant patients and a broader age range) in the future.⁵⁸

An agent that alters SMN1 expression. Onasemnogene abeparvovec-xioi, FDA approved in 2019, was the first gene-replacement therapy indicated for treating SMA in children ≤ 2 years old.⁶⁰ Treatment utilizes an AAV vector type 9 (AAV9) to deliver a functional copy of SMN1 into target motor-neuron cells, thus increasing SMN protein production and improving motor function. This AAV serotype is ideal because it crosses the blood-brain barrier. Treatment is administered as a one-time IV fusion.^38,39,43

FDA approval was based on the STR1VE (ClinicalTrial.gov Identifier: NCT03306277) phase 3 study and START (ClinicalTrial.gov Identifier: NCT02122952) phase 1 study.^61,62 START was the first trial to investigate the safety and efficacy of onasemnogene abeparvovec-xioi in SMA Type 1 infants (< 6 months old). Results demonstrated remarkable clinical benefit, including 100% permanent ventilation-free survival and a 92% (11 of 12 patients) rate of improvement in motor function. Improvement in development milestones was also observed: 92% (11 of 12 patients) could sit without support for 5 seconds and 75% (9 of 12) could sit without support for 30 seconds.^14,61,63

The efficacy of onasemnogene abeparvovec-xioi seen in STR1VE was consistent with what was observed in START. STRIVE, a phase 3 open-label, single-dose trial, examined treatment efficacy and safety in 22 symptomatic infants (< 6 months old) with SMA Type 1 (one or two SMN2 copies). The primary endpoint was 30 seconds of independent sitting and event-free survival. Patients were followed for as long as 18 months. Treatment showed statistically significant (P < .0001) improvement in motor milestone development and event-free survival, which had not been observed in SMA Type 1 historically. Approximately 59% (13 of 22 patients) could sit independently for 30 seconds at 18 months of age. At 14 months of age, 91% (20 of 22 patients) were alive and achieved independence from ventilatory support.^34,35,53

Although many clinical studies suggest that onasemnogene abeparvovec-xioi can slow disease progression, the benefits and risks of long-term effects are still unknown. A 15-year observational study is investigating the long-term therapeutic effects and potential complications of onasemnogene abeparvovec-xioi. Participants in START were invited to enroll in this long-term follow-up study (ClinicalTrial.gov Identifier: NCT04042025).^66-67
 

Duchenne muscular dystrophy

DMD is the most common muscular dystrophy of childhood. With an X-linked pattern of inheritance, DMD is seen mostly in young males (1 in every 3,500 male births).^38,39,73 DMD is caused by mutation of the dystrophin encoding gene, or DMD, on the X chromosome. Deletion of one or more exons of DMD prevents production of the dystrophin protein, which leads to muscle degeneration.^38,39,43 Common DMD deletion hotspots are exon 51 (20% of cases), exon 53 (13% of cases), exon 44 (11% of cases), and exon 45 (12% of cases).⁷⁴ Nonsense mutations, which account for another 10% of DMD cases, occur when premature termination codons are found in the DMD gene. Those mutations yield truncated dystrophin protein products.^39,66

Therapy for DMD

There are many therapeutic options for DMD, including deflazacort (Emflaza), FDA approved in 2017, which has been shown to reduce inflammation and immune system activity in DMD patients (≥ 5 years old). Deflazacort is a corticosteroid prodrug; its active metabolite acts on the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. Studies have shown that muscle strength scores over 6-12 months and average time to loss of ambulation numerically favored deflazacort over placebo.^74,75

Gene-based therapy for DMD

Mutation-specific therapeutic approaches, such as exon skipping and nonsense suppression, have shown promise for the treatment of DMD (Table 3^58-79):

• ASO-mediated exon skipping allows one or more exons to be omitted from the mutated DMD mRNA.^74,75 Effective FDA-approved ASOs include golodirsen [Vyondys 53], viltolarsen [Viltepso], and casimersen [Amondys 45].⁷⁴
• An example of therapeutic suppression of nonsense mutations is ataluren [Translarna], an investigational agent that can promote premature termination codon read-through in DMD patients.⁶⁶

Another potential treatment approach is through the use of AAV gene transfer to treat DMD. However, because DMD is too large for the AAV vector (packaging size, 5.0 kb), microdystrophin genes (3.5-4 kb, are used as an alternative to fit into a single AAV vector.^39,76

Exon skipping targeting exon 51. Eteplirsen, approved in 2016, is indicated for the treatment of DMD patients with the confirmed DMD gene mutation that is amenable to exon 51 skipping. Eteplirsen binds to exon 51 of dystrophin pre-mRNA, causing it to be skipped, thus, restoring the reading frame in patients with DMD gene mutation amenable to exon 51 skipping. This exclusion promotes dystrophin production. Though the dystrophin protein is still functional, it is shortened.^38,77 Treatment is administered IV, once a week (over 35-60 minutes). Eteplirsen’s accelerated approval was based on 3 clinical studies (ClinicalTrial.gov Identifier: NCT01396239, NCT01540409, and NCT00844597.) ^78-81 The data demonstrated an increased expression of dystrophin in skeletal muscles in some DMD patients treated with eteplirsen. Though the clinical benefit of eteplirsen (including improved motor function) was not established, it was concluded by the FDA that the data were reasonably likely to predict clinical benefit. Continued approval for this indication may depend on the verification of a clinical benefit in confirmatory trials. Ongoing clinical trials include (ClinicalTrial.gov Identifier: NCT03992430 (MIS51ON), NCT03218995, and NCT03218995).^77,81,82

Vesleteplirsen, is an investigational agent that is designed for DMD patients who are amendable to exon 51 skip-ping. The mechanism of action of vesleteplirsen appears to be similar to that of eteplirsen.⁸³ The ongoing MOMENTUM (ClinicalTrial.gov Identifier: NCT04004065) phase 2 trial is assessing the safety and tolerability of vesleteplirsen at multiple-ascending dose levels (administered via IV infusion) in 60 participants (7-21 years of age). The study consists of two parts; participants receive escalating dose levels of vesleteplirsen (every 4 weeks) for 72 weeks during part A and participants receive the selected doses from part A (every 4 weeks) for 2 years during part B. Study endpoints include the number of AEs (up to 75 weeks) and the change from baseline to week 28 in dystrophin protein level. 84 Serious AEs of reversible hypomagnesemia were observed in part B, and as a result, the study protocol was amended to include magnesium supplementation and monitoring of magnesium levels.⁸³

Exon skipping targeting exon 53. Golodirsen, FDA approved in 2019, is indicated for the treatment of DMD in patients who have a confirmed DMD mutation that is amenable to exon 53 skipping. The mechanism of action is similar to eteplirsen, however, golodirsen is designed to bind to exon 53.^38,39 Treatment is administered by IV infusion over 35-60 minutes.

Approval of golodirsen was based primarily on a two-part, phase 1/2 clinical trial (ClinicalTrial.gov Identifier: NCT02310906). Part 1 was a randomized, placebo-controlled, dose-titration study that assessed multiple-dose efficacy in 12 DMD male patients, 6 to 15 years old, with deletions that were amenable to exon 53 skipping.

Part 2 was an open-label trial in 12 DMD patients from Part 1 of the trial plus 13 newly enrolled male DMD patients who were also amenable to exon 53 skipping and who had not already received treatment. Primary endpoints were change from baseline in total distance walked during the 6-minute walk test at Week 144 and dystrophin protein levels (measured by western blot testing) at Week 48. A statistically significant increase in the mean dystrophin level was observed, from a baseline 0.10% mean dystrophin level to a 1.02% mean dystrophin level after 48 weeks of treatment (P < .001). Common reported adverse events associated with golodirsen were headache, fever, abdominal pain, rash, and dermatitis. Renal toxicity was observed in preclinical studies of golodirsen but not in clinical studies.^80,85

Viltolarsen, approved in 2020, is also indicated for the treatment of DMD in patients with deletions amenable to exon 53 skipping. The mechanism of action and administration (IV infusion over 60 minutes) are similar to that of golodirsen.

Approval of viltolarsen was based on two phase 2 clinical trials (ClinicalTrial.gov Identifier: NCT02740972 and NCT03167255) in a total of 32 patients. NCT02740972 was a randomized, double-blind, placebo-controlled, dose-finding study that evaluated the clinical efficacy of viltolarsen in 16 male DMD patients (4-9 years old) for 24 weeks.

NCT03167255 was an open-label study that evaluated the safety and tolerability of viltolarsen in DMD male patients (5-18 years old) for 192 weeks. The efficacy endpoint was the change in dystrophin production from baseline after 24 weeks of treatment. A statistically significant increase in the mean dystrophin level was observed, from a 0.6% mean dystrophin level at baseline to a 5.9% mean dystrophin level at Week 25 (P = .01). The most common adverse events observed were upper respiratory tract infection, cough, fever, and injection-site reaction.^86-87

Exon skipping targeting exon 45. Casimersen was approved in 2021 for the treatment of DMD in patients with deletions amenable to exon 45 skipping.⁸⁸ Treatment is administered by IV infusion over 30-60 minutes. Approval was based on an increase in dystrophin production in skeletal muscle in treated patients. Clinical benefit was reported in interim results from the ESSENCE (ClinicalTrial.gov Identifier: NCT02500381) study, an ongoing double-blind, placebo-controlled phase 3 trial that is evaluating the efficacy of casimersen, compared with placebo, in male participants (6-13 years old) for 48 weeks. Efficacy is based on the change from baseline dystrophin intensity level, determined by immunohistochemistry, at Week 48.

Interim results from ESSENCE show a statistically significant increase in dystrophin production in the casimersen group, from a 0.9% mean dystrophin level at baseline to a 1.7% mean dystrophin level at Week 48 (P = .004); in the control group, a 0.54% mean dystrophin level at baseline increased to a 0.76% mean dystrophin level at Week 48 (P = .09). Common adverse events have included respiratory tract infection, headache, arthralgia, fever, and oropharyngeal pain. Renal toxicity was observed in preclinical data but not in clinical studies.^60,84

Targeting nonsense mutations. Ataluren is an investigational, orally administered nonsense mutation suppression therapy (through the read-through of stop codons).³⁷ Early clinical evidence supporting the use of ataluren in DMD was seen in an open-label, dose-ranging, phase 2a study (ClinicalTrial.gov Identifier: NCT00264888) in male DMD patients (≥ 5 years old) caused by nonsense mutation. The study demonstrated a modest (61% ) increase in dystrophin expression in 23 of 38 patients after 28 days of treatment.^37,91,92

However, a phase 2b randomized, double-blind, placebo-controlled trial (ClinicalTrial.gov Identifier: NCT00592553) and a subsequent confirmatory ACT DMD phase 3 study (ClinicalTrial.gov Identifier: NCT01826487) did not meet their primary endpoint of improvement in ambulation after 48 weeks as measured by the 6-minute walk test.^37,93,94 In ACT DMD, approximately 74% of the ataluren group did not experience disease progression, compared with 56% of the control group (P = 0386), measured by a change in the 6-minute walk test, which assessed ambulatory decline.^37,95

Based on limited data showing that ataluren is effective and well tolerated, the European Medicines Agency has given conditional approval for clinical use of the drug in Europe. However, ataluren was rejected by the FDA as a candidate therapy for DMD in the United States.²² Late-stage clinical studies of ataluren are ongoing in the United States.

AAV gene transfer with microdystrophin. Limitations on traditional gene-replacement therapy prompted exploration of gene-editing strategies for treating DMD, including using AAV-based vectors to transfer microdystrophin, an engineered version of DMD, into target muscles.⁴³ The microdystrophin gene is designed to produce a functional, truncated form of dystrophin, thus improving muscular function.

There are 3 ongoing investigational microdystrophin gene therapies that are in clinical development (ClinicalTrial.gov Identifier: NCT03368742 (IGNITE DMD), NCT04281485 (CIFFREO), and NCT05096221 (EMBARK)).^38,82

IGNITE DMD is a phase 1/2 randomized, controlled, single-ascending dose trial evaluating the safety and efficacy of a SGT-001, single IV infusion of AAV9 vector containing a microdystrophin construct in DMD patients (4-17 years old) for 12 months. At the conclusion of the trial, treatment and control groups will be followed for 5 years. The primary efficacy endpoint is the change from baseline in microdystrophin protein production in muscle-biopsy material, using western blot testing.⁹⁶ Long-term interim data on biopsy findings from three patients demonstrated clinical evidence of durable microdystrophin protein expression after 2 years of treatment.^96,97

The CIFFREO trial will assess the safety and efficacy of the PF-06939926 microdystrophin gene therapy, an investigational AAV9 containing microdystrophin, in approximately 99 ambulatory DMD patients (4-7 years of age). The study is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial. The primary efficacy end-point is the change from baseline in the North Star Ambulatory Assessment (NSAA), which measures gross motor function. This will be assessed at 52 weeks; all study participants will be followed for a total of 5 years post-treatment.^98,99,100 Due to unexpected patient death (in a non-ambulatory cohort) in the phase 1b (in a non-ambulatory cohort) in the phase 1b (ClinicalTrial.gov Identifier: (NCT03362502) trial, microdystrophin gene therapy was immediately placed on clinical hold.^101,102 The amended study protocol required that all participants undergo one week of in-hospital observation after receiving treatment.¹⁰²

The EMBARK study is a global, randomized, double-blind, placebo-controlled, phase 3 trial that is evaluating the safety and efficacy of SRP-9001, which is a rAAVrh74.MHCK7.microdystrophin gene therapy. The AAV vector (rAAVrh74) contains the microdystrophin construct, driven by the skeletal and cardiac muscle–specific promoter, MHCK7.98,99 In the EMBARK study, approximately 120 participants with DMD (4-7 years of age) will be enrolled. The primary efficacy endpoint includes the change from baseline to week 52 in the NSAA total score.⁹⁹ Based on SRP-9001, data demonstrating consistent statistically significant functional improvements in NSAA total scores and timed function tests (after one-year post- treatment) in DMD patients from previous studies and an integrated analysis from multiple studies (ClinicalTrial.gov Identifier: NCT03375164, NCT03769116, and NCT04626674), the ongoing EMBARK has great promise.^103,104
 

Challenges ahead, but advancements realized

Novel gene-based therapies show significant potential for transforming the treatment of NMDs. The complex pathologies of NMDs have been a huge challenge to disease management in an area once considered unremediable by gene-based therapy. However, advancements in precision medicine – specifically, gene-delivery systems (for example, AAV9 and AAVrh74 vectors) combined with gene modification strategies (ASOs and AAV-mediated silencing) – have the potential to, first, revolutionize standards of care for sporadic and inherited NMDs and, second, significantly reduce disease burden.⁶

What will be determined to be the “best” therapeutic approach will, likely, vary from NMD to NMD; further investigation is required to determine which agents offer optimal clinical efficacy and safety profiles.⁴³ Furthermore, the key to therapeutic success will continue to be early detection and diagnosis – first, by better understanding disease pathology and drug targets and, second, by validation of reliable biomarkers that are predictive of therapeutic benefit.^4,5

To sum up, development challenges remain, but therapeutic approaches to ALS, SMA, and DMD that utilize novel gene-delivery and gene-manipulation tools show great promise.



Ms. Yewhalashet is a student in the masters of business and science program, with a concentration in healthcare economics, at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Davis is professor of practice in clinical and regulatory affairs, Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences.
 

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90. AMONDYS 45. Prescribing information. Sarepta Therapeutics Inc.; 2021. Accessed Feb 22, 2022. http://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213026lbl.pdf.

91. Finkel RS et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dys-trophy. PLoS ONE. 2013;8(12):e81302. doi:10.1371/journal.pone.0081302.

92. PTC Therapeutics. A phase 2 study of PTC124 as an oral treatment for nonsense-mutation-mediated Duchenne muscular dystrophy. Clini-calTrials.gov Identifier: NCT00264888. Updated Jan 14, 2009. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT00264888.

93. PTC Therapeutics. A phase 2B efficacy and safety study of PTC124 in subjects with nonsense-mutation-mediated Duchenne and Becker muscular dystrophy. ClinicalTrials.gov Identifier: NCT00592553. Updated Apr 7, 2020. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT00592553.

94. PTC Therapeutics. A phase 3 efficacy and safety study of ataluren in patients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01826487. Updated Aug 4, 2020. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01826487.

95. Bushby K et al; PTC124-GD-007-DMD Study Group. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014 Oct;50(4):477-87. doi:10.1002/mus.24332.

96. Solid Biosciences LLC. A randomized, controlled, open-label, single-ascending dose, phase I/II study to investigate the safety and tolerabil-ity, and efficacy of intravenous SGT-001 in male adolescents and children with Duchenne muscular dystrophy. ClinicalTrials.gov Identifier: NCT03368742. Updated Aug 24, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03368742.

97. Solid Biosciences reports 1.5-year data from patients in the ongoing IGNITE DMD phase I/II clinical trial of SGT-001. Press release. Solid Biosciences. Sep 27, 2021. Accessed Mar 2, 2022. http://www.solidbio.com/about/media/press-releases/solid-biosciences-reports-1-5-year-data-from-patients-in-the-ongoing-ignite-dmd-phase-i-ii-clinical-trial-of-sgt-001.

98. Potter RA et al. Dose-escalation study of systemically delivered rAAVrh74.MHCK7.microdystrophin in the mdx mouse model of Duchenne muscular dystrophy. Hum Gene Ther. 2021 Apr;32(7-8):375-89. doi:10.1089/hum.2019.255.

99. Sarepta Therapeutics, Inc. A Phase 3 Multinational, Randomized, Double-Blind, Placebo- Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Patients With Duchenne Muscular Dystrophy (EMBARK). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT05096221

100. Pfizer. A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF PF 06939926 FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04281485

101. Pfizer. A phase 1B multicenter open-label, single ascending dose study to evaluate the safety and tolerability of PF-06939926 in ambula-tory and non-ambulatory subjects with Duchenne muscular dystrophy. ClinicalTrials.gov Identifier: NCT03362502. Updated Mar 2, 2022. Ac-cessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03362502.

102. MS MW. Phase 3 CIFFREO DMD Gene Therapy Trial Slated to Begin in June in US. Accessed August 21, 2022. https://musculardystrophynews.com/news/phase-3-trial-of-pfizers-gene-therapy- expected-to-open-in-us-in-june/

103. SRP-9001. Parent Project Muscular Dystrophy. Accessed August 22, 2022. https://www.parentprojectmd.org/drug-development-pipeline/srp-9001-micro-dystrophin-gene- transfer/

104. Sarepta Therapeutics’ Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies | Sarepta Therapeutics, Inc. Accessed August 22, 2022. https://investorrelations.sarepta.com/news-releases/news-release- details/sarepta-therapeutics-investigational-gene-therapy-srp-9001

105. Sarepta Therapeutics, Inc. An Open-Label Safety, Tolerability, and Efficacy Study of Eteplirsen in Patients With Duchenne Muscular Dys-trophy Who Have Completed Study 4658-102.clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03985878

106. Sarepta Therapeutics, Inc. An Open-Label Safety, Tolerability, and Pharmacokinetics Study of Eteplirsen in Young Patients With Duchenne Mus-cular Dystrophy Amenable to Exon 51 Skipping. clinicaltrials.gov; 2021. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03218995

107.Sarepta Therapeutics, Inc. A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of a High Dose of Eteplirsen, Preceded by an Open-Label Dose Escalation, in Patients With Duchenne Muscular Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03992430

108. Sarepta Therapeutics, Inc. A Phase 2, Two-Part, Multiple-Ascending-Dose Study of SRP-5051 for Dose Determination, Then Dose Ex-pansion, in Patients With .gov/ct2/show/NCT02081625.

110. NS Pharma Inc. A phase II, dose finding study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT02740972. Updated Dec 7, 2021. Ac-cessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02740972.

111. NS Pharma Inc. A phase II, open-label, extension study to assess the safety and efficacy of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT03167255. Updated Nov 24, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03167255.

112. NS Pharma Inc. A phase 2 open label study to assess the safety, tolerability, and efficacy of viltolarsen in ambulant and non-ambulant boys with Duchenne muscular dystrophy (DMD) compared with natural history controls. ClinicalTrials.gov Identifier: NCT04956289. Updated Feb 1, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04956289.

113. NS Pharma Inc. A phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04060199. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04060199.

114. NS Pharma Inc. A phase 3, multi-center, open-label extension study to assess the safety and efficacy of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04768062. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04768062.

115. Sarepta Therapeutics Inc. A randomized, double-blind, placebo-controlled, dose-titration, safety, tolerability, and pharmacokinetics study followed by an open-label safety and efficacy evaluation of SRP-4045 in advanced-stage patients with Duchenne muscular dystrophy amena-ble to exon 45 skipping. ClinicalTrials.gov Identifier: NCT02530905. Updated May 17, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02530905.

116. Sarepta Therapeutics Inc. Long-term, open-label extension study for patients with Duchenne muscular dystrophy enrolled in clinical trials evaluating casimersen or golodirsen. ClinicalTrials.gov Identifier: NCT03532542. Updated Dec 20, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03532542.

117. PTC Therapeutics. A phase 2 study of the safety, pharmacokinetics, and pharmacodynamics of ataluren (PTC124®) in patients aged ≥2 to <5 years old with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT02819557. Updated Aug 28, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02819557.

118. PTC Therapeutics. Phase 2, non-interventional, clinical study to assess dystrophin levels in subjects with nonsense mutation Duchenne muscular dystrophy who have been treated with ataluren for ≥ 9 months. ClinicalTrials.gov Identifier: NCT03796637. Updated Apr 10, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03796637.

119. PTC Therapeutics. An Open-Label Study Evaluating the Safety and Pharmacokinetics of Ataluren in Children From ≥6 Months to <2 Years of Age With Nonsense Mutation Duchenne Muscular Dystrophy. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04336826 120. PTC Therapeutics. An open-label study for previously treated ataluren (PTC124®) pa-tients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01557400. Updated Nov 25, 2020. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT01557400.

121. PTC Therapeutics. An open-label, safety study for ataluren (PTC124) patients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01247207. Updated Feb 16, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT01247207.

122. PTC Therapeutics. A phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of ataluren in patients with non-sense mutation Duchenne muscular dystrophy and open-label extension. ClinicalTrials.gov Identifier: NCT03179631. Updated Feb 8, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03179631.

123. Sarepta Therapeutics, Inc. An Open-Label, Systemic Gene Delivery Study Using Commercial Process Material to Evaluate the Safety of and Expression From SRP-9001 in Subjects With Duchenne Muscular Dystrophy (ENDEAVOR). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04626674

124. Sarepta Therapeutics, Inc. Systemic Gene Delivery Phase I/IIa Clinical Trial for Duchenne Muscular Dystrophy Using RAA-Vrh74.MHCK7.Micro-Dystrophin (MicroDys-IV-001). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03375164

125. Sarepta Therapeutics Inc. A multicenter, randomized, double-blind, placebo-controlled trial for Duchenne muscular dystrophy using SRP-9001. ClinicalTrials.gov Identifier: NCT03769116. Updated Dec 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03769116.

126. Hoffmann-La Roche. A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulant Pa-tients With Spinal Muscular Atrophy. clinicaltrials.gov; 2022. Accessed September 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05115110

Neuromuscular diseases (NMDs) are a broad classification of heterogeneous groups of disorders characterized by progressive muscle weakness resulting from muscle or nerve dysfunction.¹ Diagnosis is based on symptoms and a full medical history, as well as on muscle and imaging tests (including electromyography, nerve-conduction studies, magnetic resonance imaging, muscle biopsy, and blood tests) to confirm or rule out specific NMDs.² Early diagnosis of NMDs can be difficult because symptoms overlap with those of many other diseases.

Although individually, NMDs are rare, collectively, they affect approximately 250,000 people in the United States. Disease types vary in regard to cause, symptoms, prevalence, age of onset, progression, and severity. Functional impairment from any NMD can lead to lifelong morbidities and shortened life expectancy.^1,3

Treatment options for NMDs are limited; most target symptoms, not disease progression. Although there is a need for safe and effective gene-based therapies for NMDs, there are challenges to developing and delivering such treatments that have impeded clinical success. These include a lack of understanding about disease pathology and drug targets, limited animal model systems, and few reliable biomarkers that are predictive of therapeutic success.^4,5

Amyotrophic lateral sclerosis

ALS is caused by progressive degeneration of upper- and lower-motor neurons, which eventually leads to respiratory failure and death 3 to 5 years after disease onset.^7-9 There are two subtypes: Familial ALS (10% of cases) and sporadic ALS (90% of cases). Commonly mutated ALS-associated genes^6,8 are:

• Superoxide dismutase type 1 (SOD1).
• Chromosome 9 open reading frame 72 (C9orf72).
• Transactive response DNA-binding protein 43 (TARDBP).
• Fused in sarcoma (FUS).

SOD1-targeted therapy is being studied, with early evidence of clinical success. Mutations in SOD1 account for 10% to 20% of familial ALS cases and 1% to 2% of sporadic ALS cases.^6,10 10 Mutations in C9orf72 account for 25 to 40% of familial ALS cases and 7% of sporadic ALS cases.^8,9,11 Mutations in TARDBP account for 3% of familial ALS cases and 2% of sporadic cases.¹² Mutations in FUS account for 4% of familial ALS cases and 1% of sporadic cases. Overall, these mutant proteins can trigger neurotoxicity, thus inducing motor-neuron death.^6,10
 

Treatment of ALS

Two treatments for ALS are Food and Drug Administration approved: riluzole (Rilutek), approved in 1995, and edaravone (Radicava), approved in 2017.

Riluzole is an oral anti-excitotoxic glutamate antagonist.¹¹ Approval of riluzole was based on the results of two studies that demonstrated a 2- to 3-month survival benefit.^10,14 For patients who have difficulty swallowing, an oral suspension (Tiglutik, approved in 2018) and an oral film (Exservan, approved in 2019) are available.

Edaravone is a free-radical scavenger that decreases oxidative stress and is administered intravenously (IV).^9,13,14 Findings from clinical trials suggest functional improvement or slower decline in function for some patients.

Although these two agents demonstrate modest therapeutic benefit, neither reverses progression of disease.^10,14
 

Gene-based therapy for ALS

Many non-viral strategies, including antisense oligonucleotide (ASO), monoclonal antibodies, reverse transcriptase inhibitors, and HGF gene replacement therapy are used as therapeutic approaches to SOD1, C9orf72, and FUS gene mutations in ALS patients, and are being evaluated in clinical studies^14,15 (Table 1^13-17).

• Change from baseline in CSF SOD1 protein concentration.¹⁷ Percent reduction in the total SOD1 protein level was much higher in the tofersen-treated group than in the control group (38% more than controls in the faster-progressing population; 26% more than controls in the slower-progressing population).¹⁸
• Change from baseline in neurofilament light-chain concentration in plasma.^17,18 Percent reduction in the level of neurofilament light chain was also observed to be higher in the tofersen-treated group than in the control group (67% more than controls in the faster-progressing population and 48% more than controls in the slower-progressing population).¹⁸

Because of these encouraging results, VALOR participants were moved to the ongoing open-label extension trial of tofersen (ClinicalTri-als.gov Identifier: NCT03070119), in which both groups were treated with the active agent.

These data suggest that early tofersen treatment might slow decline in faster-progressing patients and stabilize clinical function in slower-progressing patients.^18,19 Overall, most adverse events (AEs) in the trial among patients receiving active treatment were of mild or moderate severity, and were largely consistent with either disease progression or lumbar puncture–related complications.¹⁸

Because data from VALOR suggested potential benefit from tofersen, the ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) is investigating the clinical value of presymptomatic treatment and the optimal timing of initiation of therapy.^20,21 ATLAS is a phase 3, randomized, placebo-controlled trial that examines the clinical efficacy, safety, and tolerability of tofersen in presymptomatic adult carriers of SOD1 mutation who have an elevated neurofilament light-chain concentration.²¹ ATLAS will also evaluate the efficacy of tofersen when initiated before, rather than after, ALS manifests clinically. Enrollment is still open for this trial.^20,21

Latozinemab, also known as AL001, is a first-in-class monoclonal antibody, administered by IV infusion, that elevates levels of progranulin, a key regulator of the immune activity and lysosomal function in the brain.^22,23 Latozinemab limits progranulin endocytosis and degradation by sortilin inhibition.²² Progranulin gene mutations can reduce progranulin expression (by 50 to 70 percent reduction), which may cause neuro-degeneration due to abnormal accumulation of TAR-DNA-binding protein 43 (TDP-43) in the brain cells.^22,24 TDP-43 pathology has also been shown to be associated with C9orf72 mutations.²³ Although the mechanism is not fully understood, the role of progranulin deficiency in TDP-43 pathology is believed to be associated with neurodegenerative diseases like ALS.11,23,24,43 Previous animal models of chronic neurodegenera-tion have demonstrated how increased progranulin levels can be protective against TDP-43 pathology, increasing neuronal development and survival, thus potentially slowing disease progression.^23,24,43 Currently, latozinemab is being investigated in a randomized, double-blind, placebo-controlled, multicenter phase 2 trial (ClinicalTrials.gov Identifier: NCT05053035). Approximately, 45 C90rf72-associated ALS participants (≥ 18 years of age) will receive latozinemab or placebo infusions every 4 weeks (for 24 weeks). Study endpoints include safety, tolerability, PK, PD, as well as plasma, and CSF progranulin levels.²⁵ In previous studies, latozinemab demonstrated encouraging results in frontotemporal dementia (FTD) patients who carry a progranulin mutation. Because FTD was revealed to have significant genetic overlap with ALS, there is disease-modifying potential for latozinemab in ALS patients.^23,24

TPN-101 is a nucleoside analog reverse transcriptase inhibitor, administered orally, that was originally developed for human immunodeficiency virus (HIV) treatment. However, due to recent findings suggesting retrotransposon activity contributing to neurodegeneration in TDP-43 mediated diseases, including ALS and FTD, TNP-101 is being repurposed.²⁶ The safety and tolerability of TNP-101 are currently being evaluated in C9orf72-associated ALS and FTD patients (≥ 18 years of age). The study is a randomized, double-blind, placebo-controlled paral-lel-group phase 2a trial (ClinicalTrials.gov Identifier: NCT04993755) The study includes a screening period of 6 weeks, double-blind treatment period of 24 weeks, an open-label treatment period of 24 weeks, and 4 weeks of the post-treatment follow-up visit. Study endpoints include the incidence and severity of spontaneously reported treatment-emergent adverse events (TEAEs) associated with TNP-101 and placebo for a to-tal of 48 weeks.²⁷

ION363 is an investigational ASO, administered by IT injection, that selectively targets one of the FUS mutations (p.P525L), which is responsible for earlier disease onset and rapid ALS progression.^28,29 The clinical efficacy of ION363, specifically in clinical function and survival is being assessed in FUS-associated ALS patients (≥ 12 years of age). This randomized phase 3 study (ClinicalTrials.gov Identifier: NCT04768972) includes two parts; part 1 will consist of participants receiving a multi-dose regimen (1 dose every 4-12 weeks) of ION363 or placebo for 61 weeks followed by an open-label extension treatment period in part 2, which will consist of participants receiving ION363 (every 12 weeks) for 85 weeks. The primary endpoint of the study is the change from baseline to day 505 in functional impairment, using ALS Functional Rating Scale-Revised (ALSFRS-R). This measures functional disease severity, specifically in bulbar function, gross motor skills, fine motor skills, and respiratory. The score for all 12 questions can range from 0 (no function) to 4 (full function) with a total possible score of 48.³⁰

Engensis, also known as VM202, is a non-viral gene therapy, administered by intramuscular (IM) injection, that uses a plasmid to deliver the hepatocyte growth factor (HGF) gene to promote HGF protein production. The HGF protein plays a role in angiogenesis, the previous of muscle atrophy, and the promotion of neuronal survival and growth. Based on preclinical studies, increasing HGF protein production has been shown to reduce neurodegeneration, thus potentially halting or slowing ALS progression.³¹ Currently, the safety of engensis is being evaluated in ALS patients (18-80 years of age) in the REViVALS phase 2a (ClinicalTrials.gov Identifier: NCT04632225)/2b (ClinicalTrial.gov Identifier: NCT05176093).^32,33 The ReViVALS trial is a double-blind, randomized, placebo-controlled, multi-center study. The phase 2a study endpoints include the incidence of TEAEs, treatment-emergent serious adverse events (TESAEs), injection site reactions, and clinically significant labor-atory values post-treatment (engensis vs placebo group) for 180 days.³³ A phase 2b study will evaluate the long-term safety of engensis for an additional 6 months. Study endpoints include the incidence of AEs, changes from baseline in ALSFRS-R scores to evaluate improvement in muscle function, changes from baseline in quality of life using the ALS patient assessment questionnaire, time to all-cause mortality compared to placebo, etc.³²
 

Spinal muscular atrophy

SMA is a hereditary lower motor-neuron disease caused (in 95% of cases) by deletions or, less commonly, by mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5q13 that encodes the SMN protein.⁶ Reduction in expression of the SMN protein causes motor neurons to degenerate.^36-38 Because of a large inverted duplication in chromosome 5q, two variants of SMN (SMN1 and SMN2) exist on each allele. The paralog gene, SMN2, also produces the SMN protein – although at a lower level (10% to 20% of total SMN protein production) than SMN1 does.

A single nucleotide substitution in SMN2 alters splicing and suppresses transcription of exon 7, resulting in a shortened mRNA strand that yields a truncated SMN protein product.^6,37,39 SMA is classified based on age of onset and maximum motor abilities achieved, ranging from the most severe (Type 0) to mildest (Type 4) disease.^36,40 Because SMA patients lack functional SMN1 (due to polymorphisms), disease severity is determined by copy numbers of SMN2.^6,39

 

Gene-based therapy for SMA

Three FDA-approved SMN treatments demonstrate clinically meaningful benefit in SMA: SMN2-targeting nusinersen [Spinraza] and risdiplam [Evrysdi], and SMN1-targeting onasemnogene abeparvovec-xioi [Zolgensma]³⁸ Additional approaches to SMA treatment are through SMN-independent therapies, which target muscle and nerve function. Research has strongly suggested that combined SMA therapies, specifically approved SMN-targeted and investigational SMN-independent treatments, such as GYM329 (also known as RO7204239) may be the best strategy to treat all ages, stages, and types of SMA.⁴¹ (Table 2^26-41).

• Percentage of motor milestones responders, as determined using Section 2 of the Hammersmith Infant Neurological Examination–Part 2.
• Event-free survival (that is, avoidance of combined endpoint of death or permanent ventilation).

ENDEAR met the first primary efficacy outcome, demonstrating statistically significant (P < .0001) improvement in motor milestones (head control, rolling, independent sitting, and standing). By 13 months of age, approximately 51% of nusinersen-treated participants showed improvement, compared with none in the control group.^46,47

The second primary endpoint was also met, with a statistically significant (P = .005) 47% decrease in mortality or permanent ventilation use.^46-48

The NURTURE (ClinicalTrial.gov Identifier: NCT02386553) study is also investigating the efficacy and safety of nusinersen. An ongoing, open-label, supportive phase 2 trial, NURTURE is evaluating the efficacy and safety of multiple doses of nusinersen in 25 presymptomatic SMA patients (≤ 6 weeks of age). The primary endpoint of this study is time to death or respiratory intervention.⁴⁹ Interim results demonstrate that 100% of presymptomatic infants are functioning without respiratory intervention after median follow-up of 2.9 years.^46-48

Although nusinersen has been shown to be generally safe in clinical studies, development of lumbar puncture–related complications, as well as the need for sedation during IT administration, might affect treatment tolerability in some patients.³⁹

Risdiplam was approved by the FDA in 2020 as the first orally administered small-molecule treatment of SMA (for patients ≤ 2 months of age).⁵² Risdiplam is a SMN2 splicing modifier, binding to the 5’ splice site of intron 7 and exonic splicing enhancer 2 in exon 7 of SMN2 pre-mRNA. This alternative splicing increases efficiency in SMN2 gene transcription, thus increasing SMN protein production in motor-neuron cells.³⁶ An important advantage of risdiplam is the convenience of oral administration: A large percentage of SMA patients (that is, those with Type 2 disease) have severe scoliosis, which can further complicate therapy or deter patients from using a treatment that is administered through the IT route.⁴⁰

FDA approval of risdiplam was based on clinical data from two pivotal studies, FIREFISH (ClinicalTrial.gov Identifier: NCT02913482) and SUNFISH (ClinicalTrial.gov Identifier: NCT02908685).^53-54

FIREFISH is an open-label, phase 2/3 ongoing trial in infants (1-7 months of age) with SMA Type 1. The study comprises two parts; Part 1 determined the dose of risdiplam used in Part 2, which assessed the efficacy and safety of risdiplam for 24 months. The primary endpoint was the percentage of infants sitting without support for 5 seconds after 12 months of treatment using the gross motor scale of the Bayley Scales of Infant and Toddler Development–Third Edition. A statistically significant (P < .0001) therapeutic benefit was observed in motor milestones. Approximately 29% of infants achieved the motor milestone of independent sitting for 5 seconds, which had not been observed in the natural history of SMA.^53-55

SUNFISH is an ongoing randomized, double-blind, placebo-controlled trial of risdiplam in adult and pediatric patients with SMA Types 2 and 3 (2-25 years old). This phase 2/3 study comprises two parts: Part 1 determined the dose (for 12 weeks) to be used for confirmatory Part 2 (for 12 to 24 months). The primary endpoint was the change from baseline on the 32-item Motor Function Measure at 12 months. The study met its primary endpoint, demonstrating statistically significant (P = .0156) improvement in motor function scores, with a 1.36-point increase in the risdiplam group, compared with a 0.19-point decrease in the control group.^54,55

Ongoing risdiplam clinical trials also include JEWELFISH (ClinicalTrial.gov Identifier: NCT03032172) and RAINBOW (ClinicalTrial.gov Identifier: NCT03779334).^56-57 JEWELFISH is an open-label, phase 2 trial assessing the safety of risdiplam in patients (6 months to 60 years old) who received prior treatment. The study has completed recruitment; results are pending.⁵⁶ RAINBOW is an ongoing, open-label, single-arm, phase 2 trial, evaluating the clinical efficacy and safety of risdiplam in SMA-presymptomatic newborns (≤ 6 weeks old). The study is open for enrollment.⁵⁷ Overall, interim results for JEWELFISH and RAINBOW appear promising.

In addition, combined SMA therapies, specifically risdiplam and GYM329 are currently being investigated to address the underlying cause and symptoms of SMA concurrently.⁵⁸ GYM329, is an investigational anti-myostatin antibody, selectively binding preforms of myostatin - pro-myostatin and latent myostatin, thus improving muscle mass and strength for SMA patients.⁵⁹ The safety and efficacy of GYM329 in combination with risdiplam is currently being investigated in 180 ambulant participants with SMA (2-10 years of age) in the MANATEE (ClinicalTrial.gov Identifier: NCT05115110) phase 2/3 trial. The MANATEE study is a two-part, seamless, randomized, placebo-controlled, double-blind trial. Part 1 will assess the safety of the combination treatment in approximately 36 participants; participants will receive both GYM329 (every 4 weeks) by subcutaneous (SC) injection into the abdomen and risdiplam (once per day) for 24 weeks followed by a 72-week open-label treatment period. ^54,58 The outcome measures include the incidence of AEs, percentage change from baseline in the contractile area of skeletal muscle (in dominant thigh and calf), change from baseline in RHS total score, and incidence of change from baseline in serum concentration (total myostatin, free latent myostatin, and mature myostatin) etc.⁵⁴ Part 2 will be conducted on 144 participants, specifically assessing the efficacy and safety of the optimal dose of GYM329 selected from Part 1 (combined with risdiplam) for 72 weeks. Once the treatment period is completed in either part, participants can partake in a 2-year open-label extension period.^54,58 Other outcome measures include change from baseline in lean muscle mass (assessed by full body dual-energy X- ray absorptiometry (DXA) scan), in time taken to walk/run 10 meters (measured by RHS), in time taken to rise from the floor (measured by RHS), etc.⁵⁴ Overall, this combination treatment has the potential to further improve SMA patient outcomes and will be further investigated in other patient populations (including non-ambulant patients and a broader age range) in the future.⁵⁸

An agent that alters SMN1 expression. Onasemnogene abeparvovec-xioi, FDA approved in 2019, was the first gene-replacement therapy indicated for treating SMA in children ≤ 2 years old.⁶⁰ Treatment utilizes an AAV vector type 9 (AAV9) to deliver a functional copy of SMN1 into target motor-neuron cells, thus increasing SMN protein production and improving motor function. This AAV serotype is ideal because it crosses the blood-brain barrier. Treatment is administered as a one-time IV fusion.^38,39,43

FDA approval was based on the STR1VE (ClinicalTrial.gov Identifier: NCT03306277) phase 3 study and START (ClinicalTrial.gov Identifier: NCT02122952) phase 1 study.^61,62 START was the first trial to investigate the safety and efficacy of onasemnogene abeparvovec-xioi in SMA Type 1 infants (< 6 months old). Results demonstrated remarkable clinical benefit, including 100% permanent ventilation-free survival and a 92% (11 of 12 patients) rate of improvement in motor function. Improvement in development milestones was also observed: 92% (11 of 12 patients) could sit without support for 5 seconds and 75% (9 of 12) could sit without support for 30 seconds.^14,61,63

The efficacy of onasemnogene abeparvovec-xioi seen in STR1VE was consistent with what was observed in START. STRIVE, a phase 3 open-label, single-dose trial, examined treatment efficacy and safety in 22 symptomatic infants (< 6 months old) with SMA Type 1 (one or two SMN2 copies). The primary endpoint was 30 seconds of independent sitting and event-free survival. Patients were followed for as long as 18 months. Treatment showed statistically significant (P < .0001) improvement in motor milestone development and event-free survival, which had not been observed in SMA Type 1 historically. Approximately 59% (13 of 22 patients) could sit independently for 30 seconds at 18 months of age. At 14 months of age, 91% (20 of 22 patients) were alive and achieved independence from ventilatory support.^34,35,53

Although many clinical studies suggest that onasemnogene abeparvovec-xioi can slow disease progression, the benefits and risks of long-term effects are still unknown. A 15-year observational study is investigating the long-term therapeutic effects and potential complications of onasemnogene abeparvovec-xioi. Participants in START were invited to enroll in this long-term follow-up study (ClinicalTrial.gov Identifier: NCT04042025).^66-67
 

Duchenne muscular dystrophy

DMD is the most common muscular dystrophy of childhood. With an X-linked pattern of inheritance, DMD is seen mostly in young males (1 in every 3,500 male births).^38,39,73 DMD is caused by mutation of the dystrophin encoding gene, or DMD, on the X chromosome. Deletion of one or more exons of DMD prevents production of the dystrophin protein, which leads to muscle degeneration.^38,39,43 Common DMD deletion hotspots are exon 51 (20% of cases), exon 53 (13% of cases), exon 44 (11% of cases), and exon 45 (12% of cases).⁷⁴ Nonsense mutations, which account for another 10% of DMD cases, occur when premature termination codons are found in the DMD gene. Those mutations yield truncated dystrophin protein products.^39,66

Therapy for DMD

There are many therapeutic options for DMD, including deflazacort (Emflaza), FDA approved in 2017, which has been shown to reduce inflammation and immune system activity in DMD patients (≥ 5 years old). Deflazacort is a corticosteroid prodrug; its active metabolite acts on the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. Studies have shown that muscle strength scores over 6-12 months and average time to loss of ambulation numerically favored deflazacort over placebo.^74,75

Gene-based therapy for DMD

Mutation-specific therapeutic approaches, such as exon skipping and nonsense suppression, have shown promise for the treatment of DMD (Table 3^58-79):

• ASO-mediated exon skipping allows one or more exons to be omitted from the mutated DMD mRNA.^74,75 Effective FDA-approved ASOs include golodirsen [Vyondys 53], viltolarsen [Viltepso], and casimersen [Amondys 45].⁷⁴
• An example of therapeutic suppression of nonsense mutations is ataluren [Translarna], an investigational agent that can promote premature termination codon read-through in DMD patients.⁶⁶

Another potential treatment approach is through the use of AAV gene transfer to treat DMD. However, because DMD is too large for the AAV vector (packaging size, 5.0 kb), microdystrophin genes (3.5-4 kb, are used as an alternative to fit into a single AAV vector.^39,76

Exon skipping targeting exon 51. Eteplirsen, approved in 2016, is indicated for the treatment of DMD patients with the confirmed DMD gene mutation that is amenable to exon 51 skipping. Eteplirsen binds to exon 51 of dystrophin pre-mRNA, causing it to be skipped, thus, restoring the reading frame in patients with DMD gene mutation amenable to exon 51 skipping. This exclusion promotes dystrophin production. Though the dystrophin protein is still functional, it is shortened.^38,77 Treatment is administered IV, once a week (over 35-60 minutes). Eteplirsen’s accelerated approval was based on 3 clinical studies (ClinicalTrial.gov Identifier: NCT01396239, NCT01540409, and NCT00844597.) ^78-81 The data demonstrated an increased expression of dystrophin in skeletal muscles in some DMD patients treated with eteplirsen. Though the clinical benefit of eteplirsen (including improved motor function) was not established, it was concluded by the FDA that the data were reasonably likely to predict clinical benefit. Continued approval for this indication may depend on the verification of a clinical benefit in confirmatory trials. Ongoing clinical trials include (ClinicalTrial.gov Identifier: NCT03992430 (MIS51ON), NCT03218995, and NCT03218995).^77,81,82

Vesleteplirsen, is an investigational agent that is designed for DMD patients who are amendable to exon 51 skip-ping. The mechanism of action of vesleteplirsen appears to be similar to that of eteplirsen.⁸³ The ongoing MOMENTUM (ClinicalTrial.gov Identifier: NCT04004065) phase 2 trial is assessing the safety and tolerability of vesleteplirsen at multiple-ascending dose levels (administered via IV infusion) in 60 participants (7-21 years of age). The study consists of two parts; participants receive escalating dose levels of vesleteplirsen (every 4 weeks) for 72 weeks during part A and participants receive the selected doses from part A (every 4 weeks) for 2 years during part B. Study endpoints include the number of AEs (up to 75 weeks) and the change from baseline to week 28 in dystrophin protein level. 84 Serious AEs of reversible hypomagnesemia were observed in part B, and as a result, the study protocol was amended to include magnesium supplementation and monitoring of magnesium levels.⁸³

Exon skipping targeting exon 53. Golodirsen, FDA approved in 2019, is indicated for the treatment of DMD in patients who have a confirmed DMD mutation that is amenable to exon 53 skipping. The mechanism of action is similar to eteplirsen, however, golodirsen is designed to bind to exon 53.^38,39 Treatment is administered by IV infusion over 35-60 minutes.

Approval of golodirsen was based primarily on a two-part, phase 1/2 clinical trial (ClinicalTrial.gov Identifier: NCT02310906). Part 1 was a randomized, placebo-controlled, dose-titration study that assessed multiple-dose efficacy in 12 DMD male patients, 6 to 15 years old, with deletions that were amenable to exon 53 skipping.

Part 2 was an open-label trial in 12 DMD patients from Part 1 of the trial plus 13 newly enrolled male DMD patients who were also amenable to exon 53 skipping and who had not already received treatment. Primary endpoints were change from baseline in total distance walked during the 6-minute walk test at Week 144 and dystrophin protein levels (measured by western blot testing) at Week 48. A statistically significant increase in the mean dystrophin level was observed, from a baseline 0.10% mean dystrophin level to a 1.02% mean dystrophin level after 48 weeks of treatment (P < .001). Common reported adverse events associated with golodirsen were headache, fever, abdominal pain, rash, and dermatitis. Renal toxicity was observed in preclinical studies of golodirsen but not in clinical studies.^80,85

Viltolarsen, approved in 2020, is also indicated for the treatment of DMD in patients with deletions amenable to exon 53 skipping. The mechanism of action and administration (IV infusion over 60 minutes) are similar to that of golodirsen.

Approval of viltolarsen was based on two phase 2 clinical trials (ClinicalTrial.gov Identifier: NCT02740972 and NCT03167255) in a total of 32 patients. NCT02740972 was a randomized, double-blind, placebo-controlled, dose-finding study that evaluated the clinical efficacy of viltolarsen in 16 male DMD patients (4-9 years old) for 24 weeks.

NCT03167255 was an open-label study that evaluated the safety and tolerability of viltolarsen in DMD male patients (5-18 years old) for 192 weeks. The efficacy endpoint was the change in dystrophin production from baseline after 24 weeks of treatment. A statistically significant increase in the mean dystrophin level was observed, from a 0.6% mean dystrophin level at baseline to a 5.9% mean dystrophin level at Week 25 (P = .01). The most common adverse events observed were upper respiratory tract infection, cough, fever, and injection-site reaction.^86-87

Exon skipping targeting exon 45. Casimersen was approved in 2021 for the treatment of DMD in patients with deletions amenable to exon 45 skipping.⁸⁸ Treatment is administered by IV infusion over 30-60 minutes. Approval was based on an increase in dystrophin production in skeletal muscle in treated patients. Clinical benefit was reported in interim results from the ESSENCE (ClinicalTrial.gov Identifier: NCT02500381) study, an ongoing double-blind, placebo-controlled phase 3 trial that is evaluating the efficacy of casimersen, compared with placebo, in male participants (6-13 years old) for 48 weeks. Efficacy is based on the change from baseline dystrophin intensity level, determined by immunohistochemistry, at Week 48.

Interim results from ESSENCE show a statistically significant increase in dystrophin production in the casimersen group, from a 0.9% mean dystrophin level at baseline to a 1.7% mean dystrophin level at Week 48 (P = .004); in the control group, a 0.54% mean dystrophin level at baseline increased to a 0.76% mean dystrophin level at Week 48 (P = .09). Common adverse events have included respiratory tract infection, headache, arthralgia, fever, and oropharyngeal pain. Renal toxicity was observed in preclinical data but not in clinical studies.^60,84

Targeting nonsense mutations. Ataluren is an investigational, orally administered nonsense mutation suppression therapy (through the read-through of stop codons).³⁷ Early clinical evidence supporting the use of ataluren in DMD was seen in an open-label, dose-ranging, phase 2a study (ClinicalTrial.gov Identifier: NCT00264888) in male DMD patients (≥ 5 years old) caused by nonsense mutation. The study demonstrated a modest (61% ) increase in dystrophin expression in 23 of 38 patients after 28 days of treatment.^37,91,92

However, a phase 2b randomized, double-blind, placebo-controlled trial (ClinicalTrial.gov Identifier: NCT00592553) and a subsequent confirmatory ACT DMD phase 3 study (ClinicalTrial.gov Identifier: NCT01826487) did not meet their primary endpoint of improvement in ambulation after 48 weeks as measured by the 6-minute walk test.^37,93,94 In ACT DMD, approximately 74% of the ataluren group did not experience disease progression, compared with 56% of the control group (P = 0386), measured by a change in the 6-minute walk test, which assessed ambulatory decline.^37,95

Based on limited data showing that ataluren is effective and well tolerated, the European Medicines Agency has given conditional approval for clinical use of the drug in Europe. However, ataluren was rejected by the FDA as a candidate therapy for DMD in the United States.²² Late-stage clinical studies of ataluren are ongoing in the United States.

AAV gene transfer with microdystrophin. Limitations on traditional gene-replacement therapy prompted exploration of gene-editing strategies for treating DMD, including using AAV-based vectors to transfer microdystrophin, an engineered version of DMD, into target muscles.⁴³ The microdystrophin gene is designed to produce a functional, truncated form of dystrophin, thus improving muscular function.

There are 3 ongoing investigational microdystrophin gene therapies that are in clinical development (ClinicalTrial.gov Identifier: NCT03368742 (IGNITE DMD), NCT04281485 (CIFFREO), and NCT05096221 (EMBARK)).^38,82

IGNITE DMD is a phase 1/2 randomized, controlled, single-ascending dose trial evaluating the safety and efficacy of a SGT-001, single IV infusion of AAV9 vector containing a microdystrophin construct in DMD patients (4-17 years old) for 12 months. At the conclusion of the trial, treatment and control groups will be followed for 5 years. The primary efficacy endpoint is the change from baseline in microdystrophin protein production in muscle-biopsy material, using western blot testing.⁹⁶ Long-term interim data on biopsy findings from three patients demonstrated clinical evidence of durable microdystrophin protein expression after 2 years of treatment.^96,97

The CIFFREO trial will assess the safety and efficacy of the PF-06939926 microdystrophin gene therapy, an investigational AAV9 containing microdystrophin, in approximately 99 ambulatory DMD patients (4-7 years of age). The study is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial. The primary efficacy end-point is the change from baseline in the North Star Ambulatory Assessment (NSAA), which measures gross motor function. This will be assessed at 52 weeks; all study participants will be followed for a total of 5 years post-treatment.^98,99,100 Due to unexpected patient death (in a non-ambulatory cohort) in the phase 1b (in a non-ambulatory cohort) in the phase 1b (ClinicalTrial.gov Identifier: (NCT03362502) trial, microdystrophin gene therapy was immediately placed on clinical hold.^101,102 The amended study protocol required that all participants undergo one week of in-hospital observation after receiving treatment.¹⁰²

The EMBARK study is a global, randomized, double-blind, placebo-controlled, phase 3 trial that is evaluating the safety and efficacy of SRP-9001, which is a rAAVrh74.MHCK7.microdystrophin gene therapy. The AAV vector (rAAVrh74) contains the microdystrophin construct, driven by the skeletal and cardiac muscle–specific promoter, MHCK7.98,99 In the EMBARK study, approximately 120 participants with DMD (4-7 years of age) will be enrolled. The primary efficacy endpoint includes the change from baseline to week 52 in the NSAA total score.⁹⁹ Based on SRP-9001, data demonstrating consistent statistically significant functional improvements in NSAA total scores and timed function tests (after one-year post- treatment) in DMD patients from previous studies and an integrated analysis from multiple studies (ClinicalTrial.gov Identifier: NCT03375164, NCT03769116, and NCT04626674), the ongoing EMBARK has great promise.^103,104
 

Challenges ahead, but advancements realized

Novel gene-based therapies show significant potential for transforming the treatment of NMDs. The complex pathologies of NMDs have been a huge challenge to disease management in an area once considered unremediable by gene-based therapy. However, advancements in precision medicine – specifically, gene-delivery systems (for example, AAV9 and AAVrh74 vectors) combined with gene modification strategies (ASOs and AAV-mediated silencing) – have the potential to, first, revolutionize standards of care for sporadic and inherited NMDs and, second, significantly reduce disease burden.⁶

What will be determined to be the “best” therapeutic approach will, likely, vary from NMD to NMD; further investigation is required to determine which agents offer optimal clinical efficacy and safety profiles.⁴³ Furthermore, the key to therapeutic success will continue to be early detection and diagnosis – first, by better understanding disease pathology and drug targets and, second, by validation of reliable biomarkers that are predictive of therapeutic benefit.^4,5

To sum up, development challenges remain, but therapeutic approaches to ALS, SMA, and DMD that utilize novel gene-delivery and gene-manipulation tools show great promise.



Ms. Yewhalashet is a student in the masters of business and science program, with a concentration in healthcare economics, at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Davis is professor of practice in clinical and regulatory affairs, Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences.
 

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49. Biogen. An open-label study to assess the efficacy, safety, tolerability, and pharmacokinetics of multiple doses of ISIS 396443 delivered intrathecally to subjects with genetically diagnosed and presymptomatic spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT02386553. Updated Nov 18, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02386553.

50. De Vivo DC et al; NURTURE Study Group. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: In-terim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019 Nov;29(11):842-56. doi:10.1016/j.nmd.2019.09.007.

51. Why Spinraza/presymptomatic study. SPINRAZA® (nusinersen) [Internet]. Accessed Feb 22, 2022. www.spinraza.com/en_us/home/why-spinraza/presymptomatic-study.html#scroll-tabs.

52. FDA approves oral treatment for spinal muscular atrophy. U.S. Food and Drug Administration. News release. Aug 7, 2020. Accessed Mar 1, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy.

53. Hoffmann-La Roche. A two-part seamless, open-label, multicenter study to investigate the safety, tolerability, pharmacokinetics, pharmaco-dynamics and efficacy of risdiplam (RO7034067) in infants with type 1 spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT02913482. Updated Jan 21, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02913482.

54. Hoffmann-La Roche. A two-part seamless, multi-center randomized, placebo-controlled, double-blind study to investigate the safety, tolera-bility, pharmacokinetics, pharmacodynamics and efficacy of risdiplam (RO7034067) in type 2 and 3 spinal muscular atrophy patients. Clinical-Trials.gov Identifier: NCT02908685. Updated Dec 28, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02908685.

55. Genentech. Genentech’s risdiplam shows significant improvement in survival and motor milestones in infants with type 1 spinal muscular atrophy (SMA). Press release. Apr 27, 2020. Accessed Mar 1, 2022. http://www.gene.com/media/press-releases/14847/2020-04-27/genentechs-risdiplam-shows-significant-i

56. Hoffmann-La Roche. An open-label study to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics of risdiplam (RO7034067) in adult and pediatric patients with spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT03032172. Updated Jan 27, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03032172.

57. Hoffmann-La Roche. An open-label study of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT03779334. Updated Jan 27, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03779334.

58. McCall S. Update on Genentech/Roche Initiation of MANATEE Clinical Study. Cure SMA. Published October 20, 2021. Accessed August 20, 2022. https://www.curesma.org/update-on- genentech-roche-initiation-of-manatee-clinical-study/

59. Abati E, Manini A, Comi GP, Corti S. Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases. Cell Mol Life Sci. 2022;79(7):374. doi:10.1007/s00018-022-04408-w

60. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. U.S. Food and Drug Administration. News release. May 24, 2019. Accessed Mar 1, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease.

61. Novartis Gene Therapies. Phase I gene transfer clinical trial for spinal muscular atrophy type 1 delivering AVXS-101. ClinicalTrials.gov Identifier: NCT02122952. Updated Jun 14, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02122952.

62. Novartis Gene Therapies. Phase 3, open-label, single-arm, single-dose gene replacement therapy clinical trial for patients with spinal mus-cular atrophy type 1 with one or two SMN2 copies delivering AVXS-101 by intravenous infusion. ClinicalTrials.gov Identifier: NCT03306277. Updated Jun 14, 2021. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT03306277.

63. Mendell JR et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-22. doi:10.1056/NEJMoa1706198.

64. Symptomatic study results. ZOLGENSMA [Internet]. Updated Nov 2021. Accessed Mar 1, 2022. Error! Hyperlink reference not valid..

65. Novartis Gene Therapies. A global study of a single, one-time dose of AVXS-101 delivered to infants with genetically diagnosed and pre-symptomatic spinal muscular atrophy with multiple copies of SMN2. ClinicalTrials.gov Identifier: NCT03505099. Updated Jan 1, 2022. Ac-cessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03505099.

66. Chiu W et al. Current genetics and potential gene-targeting therapeutics for neuromuscular diseases. Int J Mol Sci. 2020 Dec;21(24):9589. doi:10.3390/ijms21249589.

67. Novartis Gene Therapies. A long-term follow-up study of patients in the clinical trials for spinal muscular atrophy receiving AVXS-101. Clini-calTrials.gov Identifier: NCT04042025. Updated Jun 9, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04042025.

68. Novartis Gene Therapies. Phase 3, open-label, single-arm, single-dose gene replacement therapy clinical trial for patients with spinal mus-cular atrophy type 1 with one or two SMN2 copies delivering AVXS-101 by intravenous infusion. ClinicalTrials.gov Identifier: NCT0383718. Up-dated Jan 11, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03837184.

69. Biogen. An open-label, dose escalation study to assess the safety, tolerability and dose-range finding of multiple doses of ISIS 396443 de-livered intrathecally to patients with spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT01703988. Updated Apr 13, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01703988.

70. Biogen. A study to assess the efficacy, safety, tolerability, and pharmacokinetics of multiple doses of ISIS 396443 delivered intrathecally to patients with infantile-onset spinal muscular atrophy. ClinicalTrials.gov Identifier: NCT01839656. Updated Feb 17, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01839656.

71. Biogen. An open-label extension study for patients with spinal muscular atrophy who previously participated in investigational studies of ISIS 396443. ClinicalTrials.gov Identifier: NCT02594124. Updated Nov 15, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02594124.

72. Biogen. Escalating dose and randomized, controlled study of nusinersen (BIIB058) in participants with spinal muscular atrophy. ClinicalTri-als.gov Identifier: NCT04089566. Updated Feb 24, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04089566.

73. National Center for Advancing Translational Sciences. Duchenne muscular dystrophy. Genetic and Rare Diseases Information Center. Up-dated Nov 2, 2020. Accessed Mar 1, 2022. https://rarediseases.info.nih.gov/diseases/6291/duchenne-muscular-dystrophy.

74. Matsuo M. Antisense oligonucleotide-mediated exon-skipping therapies: Precision medicine spreading from Duchenne muscular dystrophy. JMA J. 2021 Jul 15;4(3):232-40. doi:10.31662/jmaj.2021-0019.

75. FDA approves drug to treat Duchenne muscular dystrophy. U.S. Food and Drug Administration. News release. Feb 9, 2017. Accessed Mar 1, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-duchenne-muscular-dystrophy.74.

76. Duan D. Dystrophin gene replacement and gene repair therapy for Duchenne muscular dystrophy in 2016: An interview. Hum Gene Ther Clin Dev. 2016 Mar;27(1):9-18. doi:10.1089/humc.2016.001.

77. EXONDYS 51®. Parent Project Muscular Dystrophy. Accessed August 21, 2022. https://www.parentprojectmd.org/drug-development-pipeline/exondys-51/

78. Sarepta Therapeutics, Inc. A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Efficacy, Safety, Tolerability and Pharmacoki-netics Study of AVI-4658(Eteplirsen),in the Treatment of Ambulant Subjects With Duchenne Muscular Dystrophy. clinicaltrials.gov; 2020. Ac-cessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT01396239

79. Sarepta Therapeutics, Inc. Clinical Study to Assess the Safety Fo AVI-4658 in Subjects With Duchenne Muscular Dystrophy Due to a Frame-Shift Mutation Amenable to Correction by Skipping Exon 51. clinicaltrials.gov; 2015. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/study/NCT00844597

80. Sarepta Therapeutics, Inc. A 2-part, randomized, double-blind, placebo-controlled, dose-titration, safety, tolerability, and pharmacokinetics study (Part 1) followed by an open-label efficacy and safety evaluation (Part 2) of SRP-4053 in patients with Duchenne muscular dystrophy amenable to exon 53 skipping. ClinicalTrials.gov Identifier: NCT02310906. Updated Oct 19, 2020. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/results/NCT02310906.

81. Commissioner O of the. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. FDA. Published March 24, 2020. Accessed August 21, 2022. hDuchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment. clinicaltrials.gov; 2022. Accessed Au-gust 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04004065

109. National Center of Neurology and Psychiatry, Japan. Exploratory study of NS-065/NCNP-01 in Duchenne muscular dystrophy. ClinicalTri-als.gov Identifier: NCT02081625; Updated Feb 26, 2020. Accessed Mar 2, 2022. https://clinicaltrialsttps://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-drug-duchenne-muscular- dys-trophy

82. Duchenne Drug Development Pipeline. Parent Project Muscular Dystrophy. Accessed August 21, 2022. https://www.parentprojectmd.org/duchenne-drug-development-pipeline/

83. Sarepta Therapeutics Provides Update on SRP-5051 for the Treatment of Duchenne Muscular Dystrophy | Sarepta Therapeutics, Inc. Ac-cessed August 22, 2022. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics- pro-vides-update-srp-5051-treatment-duchenne

84. Sarepta Therapeutics, Inc. An Open-Label Extension Study for Patients With Duchenne Muscular Dystrophy Who Participated in Studies of SRP-5051. clinicaltrials.gov; 2021. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03675126

85. VYONDYS 53. Prescribing information. Sarepta Therapeutics Inc.; 2019. Accessed Mar 2, 2022. http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211970s000lbl.pdf.

86. NS Pharma Inc. Long-term use of viltolarsen in boys with Duchenne muscular dystrophy in clinical practice (VILT-502). ClinicalTrials.gov Identifier: NCT04687020. Updated Nov 22, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04687020.

87. VILTEPSO. Prescribing information. NS Pharma; 2020. Accessed Mar 2, 2022. http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212154s000lbl.pdf.

88. FDA approves targeted treatment for rare Duchenne muscular dystrophy mutation. U.S. Food and Drug Administration. News release. Feb 25, 2021. Accessed Mar 1, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation-0.

89. Sarepta Therapeutics Inc. A double-blind, placebo-controlled, multi-center study with an open-label extension to evaluate the efficacy and safety of SRP-4045 and SRP-4053 in patients with Duchenne muscular dystrophy. Clinicaltrials.gov Identifier: NCT02500381. Updated Aug 19, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02500381.

90. AMONDYS 45. Prescribing information. Sarepta Therapeutics Inc.; 2021. Accessed Feb 22, 2022. http://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213026lbl.pdf.

91. Finkel RS et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dys-trophy. PLoS ONE. 2013;8(12):e81302. doi:10.1371/journal.pone.0081302.

92. PTC Therapeutics. A phase 2 study of PTC124 as an oral treatment for nonsense-mutation-mediated Duchenne muscular dystrophy. Clini-calTrials.gov Identifier: NCT00264888. Updated Jan 14, 2009. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT00264888.

93. PTC Therapeutics. A phase 2B efficacy and safety study of PTC124 in subjects with nonsense-mutation-mediated Duchenne and Becker muscular dystrophy. ClinicalTrials.gov Identifier: NCT00592553. Updated Apr 7, 2020. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT00592553.

94. PTC Therapeutics. A phase 3 efficacy and safety study of ataluren in patients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01826487. Updated Aug 4, 2020. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01826487.

95. Bushby K et al; PTC124-GD-007-DMD Study Group. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014 Oct;50(4):477-87. doi:10.1002/mus.24332.

96. Solid Biosciences LLC. A randomized, controlled, open-label, single-ascending dose, phase I/II study to investigate the safety and tolerabil-ity, and efficacy of intravenous SGT-001 in male adolescents and children with Duchenne muscular dystrophy. ClinicalTrials.gov Identifier: NCT03368742. Updated Aug 24, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03368742.

97. Solid Biosciences reports 1.5-year data from patients in the ongoing IGNITE DMD phase I/II clinical trial of SGT-001. Press release. Solid Biosciences. Sep 27, 2021. Accessed Mar 2, 2022. http://www.solidbio.com/about/media/press-releases/solid-biosciences-reports-1-5-year-data-from-patients-in-the-ongoing-ignite-dmd-phase-i-ii-clinical-trial-of-sgt-001.

98. Potter RA et al. Dose-escalation study of systemically delivered rAAVrh74.MHCK7.microdystrophin in the mdx mouse model of Duchenne muscular dystrophy. Hum Gene Ther. 2021 Apr;32(7-8):375-89. doi:10.1089/hum.2019.255.

99. Sarepta Therapeutics, Inc. A Phase 3 Multinational, Randomized, Double-Blind, Placebo- Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Patients With Duchenne Muscular Dystrophy (EMBARK). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT05096221

100. Pfizer. A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF PF 06939926 FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04281485

101. Pfizer. A phase 1B multicenter open-label, single ascending dose study to evaluate the safety and tolerability of PF-06939926 in ambula-tory and non-ambulatory subjects with Duchenne muscular dystrophy. ClinicalTrials.gov Identifier: NCT03362502. Updated Mar 2, 2022. Ac-cessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03362502.

102. MS MW. Phase 3 CIFFREO DMD Gene Therapy Trial Slated to Begin in June in US. Accessed August 21, 2022. https://musculardystrophynews.com/news/phase-3-trial-of-pfizers-gene-therapy- expected-to-open-in-us-in-june/

103. SRP-9001. Parent Project Muscular Dystrophy. Accessed August 22, 2022. https://www.parentprojectmd.org/drug-development-pipeline/srp-9001-micro-dystrophin-gene- transfer/

104. Sarepta Therapeutics’ Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies | Sarepta Therapeutics, Inc. Accessed August 22, 2022. https://investorrelations.sarepta.com/news-releases/news-release- details/sarepta-therapeutics-investigational-gene-therapy-srp-9001

105. Sarepta Therapeutics, Inc. An Open-Label Safety, Tolerability, and Efficacy Study of Eteplirsen in Patients With Duchenne Muscular Dys-trophy Who Have Completed Study 4658-102.clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03985878

106. Sarepta Therapeutics, Inc. An Open-Label Safety, Tolerability, and Pharmacokinetics Study of Eteplirsen in Young Patients With Duchenne Mus-cular Dystrophy Amenable to Exon 51 Skipping. clinicaltrials.gov; 2021. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03218995

107.Sarepta Therapeutics, Inc. A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of a High Dose of Eteplirsen, Preceded by an Open-Label Dose Escalation, in Patients With Duchenne Muscular Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03992430

108. Sarepta Therapeutics, Inc. A Phase 2, Two-Part, Multiple-Ascending-Dose Study of SRP-5051 for Dose Determination, Then Dose Ex-pansion, in Patients With .gov/ct2/show/NCT02081625.

110. NS Pharma Inc. A phase II, dose finding study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT02740972. Updated Dec 7, 2021. Ac-cessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02740972.

111. NS Pharma Inc. A phase II, open-label, extension study to assess the safety and efficacy of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT03167255. Updated Nov 24, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03167255.

112. NS Pharma Inc. A phase 2 open label study to assess the safety, tolerability, and efficacy of viltolarsen in ambulant and non-ambulant boys with Duchenne muscular dystrophy (DMD) compared with natural history controls. ClinicalTrials.gov Identifier: NCT04956289. Updated Feb 1, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04956289.

113. NS Pharma Inc. A phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04060199. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04060199.

114. NS Pharma Inc. A phase 3, multi-center, open-label extension study to assess the safety and efficacy of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04768062. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04768062.

115. Sarepta Therapeutics Inc. A randomized, double-blind, placebo-controlled, dose-titration, safety, tolerability, and pharmacokinetics study followed by an open-label safety and efficacy evaluation of SRP-4045 in advanced-stage patients with Duchenne muscular dystrophy amena-ble to exon 45 skipping. ClinicalTrials.gov Identifier: NCT02530905. Updated May 17, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02530905.

116. Sarepta Therapeutics Inc. Long-term, open-label extension study for patients with Duchenne muscular dystrophy enrolled in clinical trials evaluating casimersen or golodirsen. ClinicalTrials.gov Identifier: NCT03532542. Updated Dec 20, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03532542.

117. PTC Therapeutics. A phase 2 study of the safety, pharmacokinetics, and pharmacodynamics of ataluren (PTC124®) in patients aged ≥2 to <5 years old with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT02819557. Updated Aug 28, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02819557.

118. PTC Therapeutics. Phase 2, non-interventional, clinical study to assess dystrophin levels in subjects with nonsense mutation Duchenne muscular dystrophy who have been treated with ataluren for ≥ 9 months. ClinicalTrials.gov Identifier: NCT03796637. Updated Apr 10, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03796637.

119. PTC Therapeutics. An Open-Label Study Evaluating the Safety and Pharmacokinetics of Ataluren in Children From ≥6 Months to <2 Years of Age With Nonsense Mutation Duchenne Muscular Dystrophy. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04336826 120. PTC Therapeutics. An open-label study for previously treated ataluren (PTC124®) pa-tients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01557400. Updated Nov 25, 2020. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT01557400.

121. PTC Therapeutics. An open-label, safety study for ataluren (PTC124) patients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01247207. Updated Feb 16, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT01247207.

122. PTC Therapeutics. A phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of ataluren in patients with non-sense mutation Duchenne muscular dystrophy and open-label extension. ClinicalTrials.gov Identifier: NCT03179631. Updated Feb 8, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03179631.

123. Sarepta Therapeutics, Inc. An Open-Label, Systemic Gene Delivery Study Using Commercial Process Material to Evaluate the Safety of and Expression From SRP-9001 in Subjects With Duchenne Muscular Dystrophy (ENDEAVOR). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04626674

124. Sarepta Therapeutics, Inc. Systemic Gene Delivery Phase I/IIa Clinical Trial for Duchenne Muscular Dystrophy Using RAA-Vrh74.MHCK7.Micro-Dystrophin (MicroDys-IV-001). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03375164

125. Sarepta Therapeutics Inc. A multicenter, randomized, double-blind, placebo-controlled trial for Duchenne muscular dystrophy using SRP-9001. ClinicalTrials.gov Identifier: NCT03769116. Updated Dec 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03769116.

126. Hoffmann-La Roche. A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulant Pa-tients With Spinal Muscular Atrophy. clinicaltrials.gov; 2022. Accessed September 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05115110

Neuromuscular diseases (NMDs) are a broad classification of heterogeneous groups of disorders characterized by progressive muscle weakness resulting from muscle or nerve dysfunction.¹ Diagnosis is based on symptoms and a full medical history, as well as on muscle and imaging tests (including electromyography, nerve-conduction studies, magnetic resonance imaging, muscle biopsy, and blood tests) to confirm or rule out specific NMDs.² Early diagnosis of NMDs can be difficult because symptoms overlap with those of many other diseases.

Although individually, NMDs are rare, collectively, they affect approximately 250,000 people in the United States. Disease types vary in regard to cause, symptoms, prevalence, age of onset, progression, and severity. Functional impairment from any NMD can lead to lifelong morbidities and shortened life expectancy.^1,3

Treatment options for NMDs are limited; most target symptoms, not disease progression. Although there is a need for safe and effective gene-based therapies for NMDs, there are challenges to developing and delivering such treatments that have impeded clinical success. These include a lack of understanding about disease pathology and drug targets, limited animal model systems, and few reliable biomarkers that are predictive of therapeutic success.^4,5

Amyotrophic lateral sclerosis

ALS is caused by progressive degeneration of upper- and lower-motor neurons, which eventually leads to respiratory failure and death 3 to 5 years after disease onset.^7-9 There are two subtypes: Familial ALS (10% of cases) and sporadic ALS (90% of cases). Commonly mutated ALS-associated genes^6,8 are:

• Superoxide dismutase type 1 (SOD1).
• Chromosome 9 open reading frame 72 (C9orf72).
• Transactive response DNA-binding protein 43 (TARDBP).
• Fused in sarcoma (FUS).

SOD1-targeted therapy is being studied, with early evidence of clinical success. Mutations in SOD1 account for 10% to 20% of familial ALS cases and 1% to 2% of sporadic ALS cases.^6,10 10 Mutations in C9orf72 account for 25 to 40% of familial ALS cases and 7% of sporadic ALS cases.^8,9,11 Mutations in TARDBP account for 3% of familial ALS cases and 2% of sporadic cases.¹² Mutations in FUS account for 4% of familial ALS cases and 1% of sporadic cases. Overall, these mutant proteins can trigger neurotoxicity, thus inducing motor-neuron death.^6,10
 

Treatment of ALS

Two treatments for ALS are Food and Drug Administration approved: riluzole (Rilutek), approved in 1995, and edaravone (Radicava), approved in 2017.

Riluzole is an oral anti-excitotoxic glutamate antagonist.¹¹ Approval of riluzole was based on the results of two studies that demonstrated a 2- to 3-month survival benefit.^10,14 For patients who have difficulty swallowing, an oral suspension (Tiglutik, approved in 2018) and an oral film (Exservan, approved in 2019) are available.

Edaravone is a free-radical scavenger that decreases oxidative stress and is administered intravenously (IV).^9,13,14 Findings from clinical trials suggest functional improvement or slower decline in function for some patients.

Although these two agents demonstrate modest therapeutic benefit, neither reverses progression of disease.^10,14
 

Gene-based therapy for ALS

Many non-viral strategies, including antisense oligonucleotide (ASO), monoclonal antibodies, reverse transcriptase inhibitors, and HGF gene replacement therapy are used as therapeutic approaches to SOD1, C9orf72, and FUS gene mutations in ALS patients, and are being evaluated in clinical studies^14,15 (Table 1^13-17).

• Change from baseline in CSF SOD1 protein concentration.¹⁷ Percent reduction in the total SOD1 protein level was much higher in the tofersen-treated group than in the control group (38% more than controls in the faster-progressing population; 26% more than controls in the slower-progressing population).¹⁸
• Change from baseline in neurofilament light-chain concentration in plasma.^17,18 Percent reduction in the level of neurofilament light chain was also observed to be higher in the tofersen-treated group than in the control group (67% more than controls in the faster-progressing population and 48% more than controls in the slower-progressing population).¹⁸

Because of these encouraging results, VALOR participants were moved to the ongoing open-label extension trial of tofersen (ClinicalTri-als.gov Identifier: NCT03070119), in which both groups were treated with the active agent.

These data suggest that early tofersen treatment might slow decline in faster-progressing patients and stabilize clinical function in slower-progressing patients.^18,19 Overall, most adverse events (AEs) in the trial among patients receiving active treatment were of mild or moderate severity, and were largely consistent with either disease progression or lumbar puncture–related complications.¹⁸

Because data from VALOR suggested potential benefit from tofersen, the ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) is investigating the clinical value of presymptomatic treatment and the optimal timing of initiation of therapy.^20,21 ATLAS is a phase 3, randomized, placebo-controlled trial that examines the clinical efficacy, safety, and tolerability of tofersen in presymptomatic adult carriers of SOD1 mutation who have an elevated neurofilament light-chain concentration.²¹ ATLAS will also evaluate the efficacy of tofersen when initiated before, rather than after, ALS manifests clinically. Enrollment is still open for this trial.^20,21

Latozinemab, also known as AL001, is a first-in-class monoclonal antibody, administered by IV infusion, that elevates levels of progranulin, a key regulator of the immune activity and lysosomal function in the brain.^22,23 Latozinemab limits progranulin endocytosis and degradation by sortilin inhibition.²² Progranulin gene mutations can reduce progranulin expression (by 50 to 70 percent reduction), which may cause neuro-degeneration due to abnormal accumulation of TAR-DNA-binding protein 43 (TDP-43) in the brain cells.^22,24 TDP-43 pathology has also been shown to be associated with C9orf72 mutations.²³ Although the mechanism is not fully understood, the role of progranulin deficiency in TDP-43 pathology is believed to be associated with neurodegenerative diseases like ALS.11,23,24,43 Previous animal models of chronic neurodegenera-tion have demonstrated how increased progranulin levels can be protective against TDP-43 pathology, increasing neuronal development and survival, thus potentially slowing disease progression.^23,24,43 Currently, latozinemab is being investigated in a randomized, double-blind, placebo-controlled, multicenter phase 2 trial (ClinicalTrials.gov Identifier: NCT05053035). Approximately, 45 C90rf72-associated ALS participants (≥ 18 years of age) will receive latozinemab or placebo infusions every 4 weeks (for 24 weeks). Study endpoints include safety, tolerability, PK, PD, as well as plasma, and CSF progranulin levels.²⁵ In previous studies, latozinemab demonstrated encouraging results in frontotemporal dementia (FTD) patients who carry a progranulin mutation. Because FTD was revealed to have significant genetic overlap with ALS, there is disease-modifying potential for latozinemab in ALS patients.^23,24

TPN-101 is a nucleoside analog reverse transcriptase inhibitor, administered orally, that was originally developed for human immunodeficiency virus (HIV) treatment. However, due to recent findings suggesting retrotransposon activity contributing to neurodegeneration in TDP-43 mediated diseases, including ALS and FTD, TNP-101 is being repurposed.²⁶ The safety and tolerability of TNP-101 are currently being evaluated in C9orf72-associated ALS and FTD patients (≥ 18 years of age). The study is a randomized, double-blind, placebo-controlled paral-lel-group phase 2a trial (ClinicalTrials.gov Identifier: NCT04993755) The study includes a screening period of 6 weeks, double-blind treatment period of 24 weeks, an open-label treatment period of 24 weeks, and 4 weeks of the post-treatment follow-up visit. Study endpoints include the incidence and severity of spontaneously reported treatment-emergent adverse events (TEAEs) associated with TNP-101 and placebo for a to-tal of 48 weeks.²⁷

ION363 is an investigational ASO, administered by IT injection, that selectively targets one of the FUS mutations (p.P525L), which is responsible for earlier disease onset and rapid ALS progression.^28,29 The clinical efficacy of ION363, specifically in clinical function and survival is being assessed in FUS-associated ALS patients (≥ 12 years of age). This randomized phase 3 study (ClinicalTrials.gov Identifier: NCT04768972) includes two parts; part 1 will consist of participants receiving a multi-dose regimen (1 dose every 4-12 weeks) of ION363 or placebo for 61 weeks followed by an open-label extension treatment period in part 2, which will consist of participants receiving ION363 (every 12 weeks) for 85 weeks. The primary endpoint of the study is the change from baseline to day 505 in functional impairment, using ALS Functional Rating Scale-Revised (ALSFRS-R). This measures functional disease severity, specifically in bulbar function, gross motor skills, fine motor skills, and respiratory. The score for all 12 questions can range from 0 (no function) to 4 (full function) with a total possible score of 48.³⁰

Engensis, also known as VM202, is a non-viral gene therapy, administered by intramuscular (IM) injection, that uses a plasmid to deliver the hepatocyte growth factor (HGF) gene to promote HGF protein production. The HGF protein plays a role in angiogenesis, the previous of muscle atrophy, and the promotion of neuronal survival and growth. Based on preclinical studies, increasing HGF protein production has been shown to reduce neurodegeneration, thus potentially halting or slowing ALS progression.³¹ Currently, the safety of engensis is being evaluated in ALS patients (18-80 years of age) in the REViVALS phase 2a (ClinicalTrials.gov Identifier: NCT04632225)/2b (ClinicalTrial.gov Identifier: NCT05176093).^32,33 The ReViVALS trial is a double-blind, randomized, placebo-controlled, multi-center study. The phase 2a study endpoints include the incidence of TEAEs, treatment-emergent serious adverse events (TESAEs), injection site reactions, and clinically significant labor-atory values post-treatment (engensis vs placebo group) for 180 days.³³ A phase 2b study will evaluate the long-term safety of engensis for an additional 6 months. Study endpoints include the incidence of AEs, changes from baseline in ALSFRS-R scores to evaluate improvement in muscle function, changes from baseline in quality of life using the ALS patient assessment questionnaire, time to all-cause mortality compared to placebo, etc.³²
 

Spinal muscular atrophy

SMA is a hereditary lower motor-neuron disease caused (in 95% of cases) by deletions or, less commonly, by mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5q13 that encodes the SMN protein.⁶ Reduction in expression of the SMN protein causes motor neurons to degenerate.^36-38 Because of a large inverted duplication in chromosome 5q, two variants of SMN (SMN1 and SMN2) exist on each allele. The paralog gene, SMN2, also produces the SMN protein – although at a lower level (10% to 20% of total SMN protein production) than SMN1 does.

A single nucleotide substitution in SMN2 alters splicing and suppresses transcription of exon 7, resulting in a shortened mRNA strand that yields a truncated SMN protein product.^6,37,39 SMA is classified based on age of onset and maximum motor abilities achieved, ranging from the most severe (Type 0) to mildest (Type 4) disease.^36,40 Because SMA patients lack functional SMN1 (due to polymorphisms), disease severity is determined by copy numbers of SMN2.^6,39

 

Gene-based therapy for SMA

Three FDA-approved SMN treatments demonstrate clinically meaningful benefit in SMA: SMN2-targeting nusinersen [Spinraza] and risdiplam [Evrysdi], and SMN1-targeting onasemnogene abeparvovec-xioi [Zolgensma]³⁸ Additional approaches to SMA treatment are through SMN-independent therapies, which target muscle and nerve function. Research has strongly suggested that combined SMA therapies, specifically approved SMN-targeted and investigational SMN-independent treatments, such as GYM329 (also known as RO7204239) may be the best strategy to treat all ages, stages, and types of SMA.⁴¹ (Table 2^26-41).

• Percentage of motor milestones responders, as determined using Section 2 of the Hammersmith Infant Neurological Examination–Part 2.
• Event-free survival (that is, avoidance of combined endpoint of death or permanent ventilation).

ENDEAR met the first primary efficacy outcome, demonstrating statistically significant (P < .0001) improvement in motor milestones (head control, rolling, independent sitting, and standing). By 13 months of age, approximately 51% of nusinersen-treated participants showed improvement, compared with none in the control group.^46,47

The second primary endpoint was also met, with a statistically significant (P = .005) 47% decrease in mortality or permanent ventilation use.^46-48

The NURTURE (ClinicalTrial.gov Identifier: NCT02386553) study is also investigating the efficacy and safety of nusinersen. An ongoing, open-label, supportive phase 2 trial, NURTURE is evaluating the efficacy and safety of multiple doses of nusinersen in 25 presymptomatic SMA patients (≤ 6 weeks of age). The primary endpoint of this study is time to death or respiratory intervention.⁴⁹ Interim results demonstrate that 100% of presymptomatic infants are functioning without respiratory intervention after median follow-up of 2.9 years.^46-48

Although nusinersen has been shown to be generally safe in clinical studies, development of lumbar puncture–related complications, as well as the need for sedation during IT administration, might affect treatment tolerability in some patients.³⁹

Risdiplam was approved by the FDA in 2020 as the first orally administered small-molecule treatment of SMA (for patients ≤ 2 months of age).⁵² Risdiplam is a SMN2 splicing modifier, binding to the 5’ splice site of intron 7 and exonic splicing enhancer 2 in exon 7 of SMN2 pre-mRNA. This alternative splicing increases efficiency in SMN2 gene transcription, thus increasing SMN protein production in motor-neuron cells.³⁶ An important advantage of risdiplam is the convenience of oral administration: A large percentage of SMA patients (that is, those with Type 2 disease) have severe scoliosis, which can further complicate therapy or deter patients from using a treatment that is administered through the IT route.⁴⁰

FDA approval of risdiplam was based on clinical data from two pivotal studies, FIREFISH (ClinicalTrial.gov Identifier: NCT02913482) and SUNFISH (ClinicalTrial.gov Identifier: NCT02908685).^53-54

FIREFISH is an open-label, phase 2/3 ongoing trial in infants (1-7 months of age) with SMA Type 1. The study comprises two parts; Part 1 determined the dose of risdiplam used in Part 2, which assessed the efficacy and safety of risdiplam for 24 months. The primary endpoint was the percentage of infants sitting without support for 5 seconds after 12 months of treatment using the gross motor scale of the Bayley Scales of Infant and Toddler Development–Third Edition. A statistically significant (P < .0001) therapeutic benefit was observed in motor milestones. Approximately 29% of infants achieved the motor milestone of independent sitting for 5 seconds, which had not been observed in the natural history of SMA.^53-55

SUNFISH is an ongoing randomized, double-blind, placebo-controlled trial of risdiplam in adult and pediatric patients with SMA Types 2 and 3 (2-25 years old). This phase 2/3 study comprises two parts: Part 1 determined the dose (for 12 weeks) to be used for confirmatory Part 2 (for 12 to 24 months). The primary endpoint was the change from baseline on the 32-item Motor Function Measure at 12 months. The study met its primary endpoint, demonstrating statistically significant (P = .0156) improvement in motor function scores, with a 1.36-point increase in the risdiplam group, compared with a 0.19-point decrease in the control group.^54,55

Ongoing risdiplam clinical trials also include JEWELFISH (ClinicalTrial.gov Identifier: NCT03032172) and RAINBOW (ClinicalTrial.gov Identifier: NCT03779334).^56-57 JEWELFISH is an open-label, phase 2 trial assessing the safety of risdiplam in patients (6 months to 60 years old) who received prior treatment. The study has completed recruitment; results are pending.⁵⁶ RAINBOW is an ongoing, open-label, single-arm, phase 2 trial, evaluating the clinical efficacy and safety of risdiplam in SMA-presymptomatic newborns (≤ 6 weeks old). The study is open for enrollment.⁵⁷ Overall, interim results for JEWELFISH and RAINBOW appear promising.

In addition, combined SMA therapies, specifically risdiplam and GYM329 are currently being investigated to address the underlying cause and symptoms of SMA concurrently.⁵⁸ GYM329, is an investigational anti-myostatin antibody, selectively binding preforms of myostatin - pro-myostatin and latent myostatin, thus improving muscle mass and strength for SMA patients.⁵⁹ The safety and efficacy of GYM329 in combination with risdiplam is currently being investigated in 180 ambulant participants with SMA (2-10 years of age) in the MANATEE (ClinicalTrial.gov Identifier: NCT05115110) phase 2/3 trial. The MANATEE study is a two-part, seamless, randomized, placebo-controlled, double-blind trial. Part 1 will assess the safety of the combination treatment in approximately 36 participants; participants will receive both GYM329 (every 4 weeks) by subcutaneous (SC) injection into the abdomen and risdiplam (once per day) for 24 weeks followed by a 72-week open-label treatment period. ^54,58 The outcome measures include the incidence of AEs, percentage change from baseline in the contractile area of skeletal muscle (in dominant thigh and calf), change from baseline in RHS total score, and incidence of change from baseline in serum concentration (total myostatin, free latent myostatin, and mature myostatin) etc.⁵⁴ Part 2 will be conducted on 144 participants, specifically assessing the efficacy and safety of the optimal dose of GYM329 selected from Part 1 (combined with risdiplam) for 72 weeks. Once the treatment period is completed in either part, participants can partake in a 2-year open-label extension period.^54,58 Other outcome measures include change from baseline in lean muscle mass (assessed by full body dual-energy X- ray absorptiometry (DXA) scan), in time taken to walk/run 10 meters (measured by RHS), in time taken to rise from the floor (measured by RHS), etc.⁵⁴ Overall, this combination treatment has the potential to further improve SMA patient outcomes and will be further investigated in other patient populations (including non-ambulant patients and a broader age range) in the future.⁵⁸

An agent that alters SMN1 expression. Onasemnogene abeparvovec-xioi, FDA approved in 2019, was the first gene-replacement therapy indicated for treating SMA in children ≤ 2 years old.⁶⁰ Treatment utilizes an AAV vector type 9 (AAV9) to deliver a functional copy of SMN1 into target motor-neuron cells, thus increasing SMN protein production and improving motor function. This AAV serotype is ideal because it crosses the blood-brain barrier. Treatment is administered as a one-time IV fusion.^38,39,43

FDA approval was based on the STR1VE (ClinicalTrial.gov Identifier: NCT03306277) phase 3 study and START (ClinicalTrial.gov Identifier: NCT02122952) phase 1 study.^61,62 START was the first trial to investigate the safety and efficacy of onasemnogene abeparvovec-xioi in SMA Type 1 infants (< 6 months old). Results demonstrated remarkable clinical benefit, including 100% permanent ventilation-free survival and a 92% (11 of 12 patients) rate of improvement in motor function. Improvement in development milestones was also observed: 92% (11 of 12 patients) could sit without support for 5 seconds and 75% (9 of 12) could sit without support for 30 seconds.^14,61,63

The efficacy of onasemnogene abeparvovec-xioi seen in STR1VE was consistent with what was observed in START. STRIVE, a phase 3 open-label, single-dose trial, examined treatment efficacy and safety in 22 symptomatic infants (< 6 months old) with SMA Type 1 (one or two SMN2 copies). The primary endpoint was 30 seconds of independent sitting and event-free survival. Patients were followed for as long as 18 months. Treatment showed statistically significant (P < .0001) improvement in motor milestone development and event-free survival, which had not been observed in SMA Type 1 historically. Approximately 59% (13 of 22 patients) could sit independently for 30 seconds at 18 months of age. At 14 months of age, 91% (20 of 22 patients) were alive and achieved independence from ventilatory support.^34,35,53

Although many clinical studies suggest that onasemnogene abeparvovec-xioi can slow disease progression, the benefits and risks of long-term effects are still unknown. A 15-year observational study is investigating the long-term therapeutic effects and potential complications of onasemnogene abeparvovec-xioi. Participants in START were invited to enroll in this long-term follow-up study (ClinicalTrial.gov Identifier: NCT04042025).^66-67
 

Duchenne muscular dystrophy

DMD is the most common muscular dystrophy of childhood. With an X-linked pattern of inheritance, DMD is seen mostly in young males (1 in every 3,500 male births).^38,39,73 DMD is caused by mutation of the dystrophin encoding gene, or DMD, on the X chromosome. Deletion of one or more exons of DMD prevents production of the dystrophin protein, which leads to muscle degeneration.^38,39,43 Common DMD deletion hotspots are exon 51 (20% of cases), exon 53 (13% of cases), exon 44 (11% of cases), and exon 45 (12% of cases).⁷⁴ Nonsense mutations, which account for another 10% of DMD cases, occur when premature termination codons are found in the DMD gene. Those mutations yield truncated dystrophin protein products.^39,66

Therapy for DMD

There are many therapeutic options for DMD, including deflazacort (Emflaza), FDA approved in 2017, which has been shown to reduce inflammation and immune system activity in DMD patients (≥ 5 years old). Deflazacort is a corticosteroid prodrug; its active metabolite acts on the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. Studies have shown that muscle strength scores over 6-12 months and average time to loss of ambulation numerically favored deflazacort over placebo.^74,75

Gene-based therapy for DMD

Mutation-specific therapeutic approaches, such as exon skipping and nonsense suppression, have shown promise for the treatment of DMD (Table 3^58-79):

• ASO-mediated exon skipping allows one or more exons to be omitted from the mutated DMD mRNA.^74,75 Effective FDA-approved ASOs include golodirsen [Vyondys 53], viltolarsen [Viltepso], and casimersen [Amondys 45].⁷⁴
• An example of therapeutic suppression of nonsense mutations is ataluren [Translarna], an investigational agent that can promote premature termination codon read-through in DMD patients.⁶⁶

Another potential treatment approach is through the use of AAV gene transfer to treat DMD. However, because DMD is too large for the AAV vector (packaging size, 5.0 kb), microdystrophin genes (3.5-4 kb, are used as an alternative to fit into a single AAV vector.^39,76

Exon skipping targeting exon 51. Eteplirsen, approved in 2016, is indicated for the treatment of DMD patients with the confirmed DMD gene mutation that is amenable to exon 51 skipping. Eteplirsen binds to exon 51 of dystrophin pre-mRNA, causing it to be skipped, thus, restoring the reading frame in patients with DMD gene mutation amenable to exon 51 skipping. This exclusion promotes dystrophin production. Though the dystrophin protein is still functional, it is shortened.^38,77 Treatment is administered IV, once a week (over 35-60 minutes). Eteplirsen’s accelerated approval was based on 3 clinical studies (ClinicalTrial.gov Identifier: NCT01396239, NCT01540409, and NCT00844597.) ^78-81 The data demonstrated an increased expression of dystrophin in skeletal muscles in some DMD patients treated with eteplirsen. Though the clinical benefit of eteplirsen (including improved motor function) was not established, it was concluded by the FDA that the data were reasonably likely to predict clinical benefit. Continued approval for this indication may depend on the verification of a clinical benefit in confirmatory trials. Ongoing clinical trials include (ClinicalTrial.gov Identifier: NCT03992430 (MIS51ON), NCT03218995, and NCT03218995).^77,81,82

Vesleteplirsen, is an investigational agent that is designed for DMD patients who are amendable to exon 51 skip-ping. The mechanism of action of vesleteplirsen appears to be similar to that of eteplirsen.⁸³ The ongoing MOMENTUM (ClinicalTrial.gov Identifier: NCT04004065) phase 2 trial is assessing the safety and tolerability of vesleteplirsen at multiple-ascending dose levels (administered via IV infusion) in 60 participants (7-21 years of age). The study consists of two parts; participants receive escalating dose levels of vesleteplirsen (every 4 weeks) for 72 weeks during part A and participants receive the selected doses from part A (every 4 weeks) for 2 years during part B. Study endpoints include the number of AEs (up to 75 weeks) and the change from baseline to week 28 in dystrophin protein level. 84 Serious AEs of reversible hypomagnesemia were observed in part B, and as a result, the study protocol was amended to include magnesium supplementation and monitoring of magnesium levels.⁸³

Exon skipping targeting exon 53. Golodirsen, FDA approved in 2019, is indicated for the treatment of DMD in patients who have a confirmed DMD mutation that is amenable to exon 53 skipping. The mechanism of action is similar to eteplirsen, however, golodirsen is designed to bind to exon 53.^38,39 Treatment is administered by IV infusion over 35-60 minutes.

Approval of golodirsen was based primarily on a two-part, phase 1/2 clinical trial (ClinicalTrial.gov Identifier: NCT02310906). Part 1 was a randomized, placebo-controlled, dose-titration study that assessed multiple-dose efficacy in 12 DMD male patients, 6 to 15 years old, with deletions that were amenable to exon 53 skipping.

Part 2 was an open-label trial in 12 DMD patients from Part 1 of the trial plus 13 newly enrolled male DMD patients who were also amenable to exon 53 skipping and who had not already received treatment. Primary endpoints were change from baseline in total distance walked during the 6-minute walk test at Week 144 and dystrophin protein levels (measured by western blot testing) at Week 48. A statistically significant increase in the mean dystrophin level was observed, from a baseline 0.10% mean dystrophin level to a 1.02% mean dystrophin level after 48 weeks of treatment (P < .001). Common reported adverse events associated with golodirsen were headache, fever, abdominal pain, rash, and dermatitis. Renal toxicity was observed in preclinical studies of golodirsen but not in clinical studies.^80,85

Viltolarsen, approved in 2020, is also indicated for the treatment of DMD in patients with deletions amenable to exon 53 skipping. The mechanism of action and administration (IV infusion over 60 minutes) are similar to that of golodirsen.

Approval of viltolarsen was based on two phase 2 clinical trials (ClinicalTrial.gov Identifier: NCT02740972 and NCT03167255) in a total of 32 patients. NCT02740972 was a randomized, double-blind, placebo-controlled, dose-finding study that evaluated the clinical efficacy of viltolarsen in 16 male DMD patients (4-9 years old) for 24 weeks.

NCT03167255 was an open-label study that evaluated the safety and tolerability of viltolarsen in DMD male patients (5-18 years old) for 192 weeks. The efficacy endpoint was the change in dystrophin production from baseline after 24 weeks of treatment. A statistically significant increase in the mean dystrophin level was observed, from a 0.6% mean dystrophin level at baseline to a 5.9% mean dystrophin level at Week 25 (P = .01). The most common adverse events observed were upper respiratory tract infection, cough, fever, and injection-site reaction.^86-87

Exon skipping targeting exon 45. Casimersen was approved in 2021 for the treatment of DMD in patients with deletions amenable to exon 45 skipping.⁸⁸ Treatment is administered by IV infusion over 30-60 minutes. Approval was based on an increase in dystrophin production in skeletal muscle in treated patients. Clinical benefit was reported in interim results from the ESSENCE (ClinicalTrial.gov Identifier: NCT02500381) study, an ongoing double-blind, placebo-controlled phase 3 trial that is evaluating the efficacy of casimersen, compared with placebo, in male participants (6-13 years old) for 48 weeks. Efficacy is based on the change from baseline dystrophin intensity level, determined by immunohistochemistry, at Week 48.

Interim results from ESSENCE show a statistically significant increase in dystrophin production in the casimersen group, from a 0.9% mean dystrophin level at baseline to a 1.7% mean dystrophin level at Week 48 (P = .004); in the control group, a 0.54% mean dystrophin level at baseline increased to a 0.76% mean dystrophin level at Week 48 (P = .09). Common adverse events have included respiratory tract infection, headache, arthralgia, fever, and oropharyngeal pain. Renal toxicity was observed in preclinical data but not in clinical studies.^60,84

Targeting nonsense mutations. Ataluren is an investigational, orally administered nonsense mutation suppression therapy (through the read-through of stop codons).³⁷ Early clinical evidence supporting the use of ataluren in DMD was seen in an open-label, dose-ranging, phase 2a study (ClinicalTrial.gov Identifier: NCT00264888) in male DMD patients (≥ 5 years old) caused by nonsense mutation. The study demonstrated a modest (61% ) increase in dystrophin expression in 23 of 38 patients after 28 days of treatment.^37,91,92

However, a phase 2b randomized, double-blind, placebo-controlled trial (ClinicalTrial.gov Identifier: NCT00592553) and a subsequent confirmatory ACT DMD phase 3 study (ClinicalTrial.gov Identifier: NCT01826487) did not meet their primary endpoint of improvement in ambulation after 48 weeks as measured by the 6-minute walk test.^37,93,94 In ACT DMD, approximately 74% of the ataluren group did not experience disease progression, compared with 56% of the control group (P = 0386), measured by a change in the 6-minute walk test, which assessed ambulatory decline.^37,95

Based on limited data showing that ataluren is effective and well tolerated, the European Medicines Agency has given conditional approval for clinical use of the drug in Europe. However, ataluren was rejected by the FDA as a candidate therapy for DMD in the United States.²² Late-stage clinical studies of ataluren are ongoing in the United States.

AAV gene transfer with microdystrophin. Limitations on traditional gene-replacement therapy prompted exploration of gene-editing strategies for treating DMD, including using AAV-based vectors to transfer microdystrophin, an engineered version of DMD, into target muscles.⁴³ The microdystrophin gene is designed to produce a functional, truncated form of dystrophin, thus improving muscular function.

There are 3 ongoing investigational microdystrophin gene therapies that are in clinical development (ClinicalTrial.gov Identifier: NCT03368742 (IGNITE DMD), NCT04281485 (CIFFREO), and NCT05096221 (EMBARK)).^38,82

IGNITE DMD is a phase 1/2 randomized, controlled, single-ascending dose trial evaluating the safety and efficacy of a SGT-001, single IV infusion of AAV9 vector containing a microdystrophin construct in DMD patients (4-17 years old) for 12 months. At the conclusion of the trial, treatment and control groups will be followed for 5 years. The primary efficacy endpoint is the change from baseline in microdystrophin protein production in muscle-biopsy material, using western blot testing.⁹⁶ Long-term interim data on biopsy findings from three patients demonstrated clinical evidence of durable microdystrophin protein expression after 2 years of treatment.^96,97

The CIFFREO trial will assess the safety and efficacy of the PF-06939926 microdystrophin gene therapy, an investigational AAV9 containing microdystrophin, in approximately 99 ambulatory DMD patients (4-7 years of age). The study is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial. The primary efficacy end-point is the change from baseline in the North Star Ambulatory Assessment (NSAA), which measures gross motor function. This will be assessed at 52 weeks; all study participants will be followed for a total of 5 years post-treatment.^98,99,100 Due to unexpected patient death (in a non-ambulatory cohort) in the phase 1b (in a non-ambulatory cohort) in the phase 1b (ClinicalTrial.gov Identifier: (NCT03362502) trial, microdystrophin gene therapy was immediately placed on clinical hold.^101,102 The amended study protocol required that all participants undergo one week of in-hospital observation after receiving treatment.¹⁰²

The EMBARK study is a global, randomized, double-blind, placebo-controlled, phase 3 trial that is evaluating the safety and efficacy of SRP-9001, which is a rAAVrh74.MHCK7.microdystrophin gene therapy. The AAV vector (rAAVrh74) contains the microdystrophin construct, driven by the skeletal and cardiac muscle–specific promoter, MHCK7.98,99 In the EMBARK study, approximately 120 participants with DMD (4-7 years of age) will be enrolled. The primary efficacy endpoint includes the change from baseline to week 52 in the NSAA total score.⁹⁹ Based on SRP-9001, data demonstrating consistent statistically significant functional improvements in NSAA total scores and timed function tests (after one-year post- treatment) in DMD patients from previous studies and an integrated analysis from multiple studies (ClinicalTrial.gov Identifier: NCT03375164, NCT03769116, and NCT04626674), the ongoing EMBARK has great promise.^103,104
 

Challenges ahead, but advancements realized

Novel gene-based therapies show significant potential for transforming the treatment of NMDs. The complex pathologies of NMDs have been a huge challenge to disease management in an area once considered unremediable by gene-based therapy. However, advancements in precision medicine – specifically, gene-delivery systems (for example, AAV9 and AAVrh74 vectors) combined with gene modification strategies (ASOs and AAV-mediated silencing) – have the potential to, first, revolutionize standards of care for sporadic and inherited NMDs and, second, significantly reduce disease burden.⁶

What will be determined to be the “best” therapeutic approach will, likely, vary from NMD to NMD; further investigation is required to determine which agents offer optimal clinical efficacy and safety profiles.⁴³ Furthermore, the key to therapeutic success will continue to be early detection and diagnosis – first, by better understanding disease pathology and drug targets and, second, by validation of reliable biomarkers that are predictive of therapeutic benefit.^4,5

To sum up, development challenges remain, but therapeutic approaches to ALS, SMA, and DMD that utilize novel gene-delivery and gene-manipulation tools show great promise.



Ms. Yewhalashet is a student in the masters of business and science program, with a concentration in healthcare economics, at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Davis is professor of practice in clinical and regulatory affairs, Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences.
 

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107.Sarepta Therapeutics, Inc. A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of a High Dose of Eteplirsen, Preceded by an Open-Label Dose Escalation, in Patients With Duchenne Muscular Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03992430

108. Sarepta Therapeutics, Inc. A Phase 2, Two-Part, Multiple-Ascending-Dose Study of SRP-5051 for Dose Determination, Then Dose Ex-pansion, in Patients With .gov/ct2/show/NCT02081625.

110. NS Pharma Inc. A phase II, dose finding study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT02740972. Updated Dec 7, 2021. Ac-cessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02740972.

111. NS Pharma Inc. A phase II, open-label, extension study to assess the safety and efficacy of NS-065/NCNP-01 in boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT03167255. Updated Nov 24, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03167255.

112. NS Pharma Inc. A phase 2 open label study to assess the safety, tolerability, and efficacy of viltolarsen in ambulant and non-ambulant boys with Duchenne muscular dystrophy (DMD) compared with natural history controls. ClinicalTrials.gov Identifier: NCT04956289. Updated Feb 1, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04956289.

113. NS Pharma Inc. A phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04060199. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04060199.

114. NS Pharma Inc. A phase 3, multi-center, open-label extension study to assess the safety and efficacy of viltolarsen in ambulant boys with Duchenne muscular dystrophy (DMD). ClinicalTrials.gov Identifier: NCT04768062. Updated Nov 16, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04768062.

115. Sarepta Therapeutics Inc. A randomized, double-blind, placebo-controlled, dose-titration, safety, tolerability, and pharmacokinetics study followed by an open-label safety and efficacy evaluation of SRP-4045 in advanced-stage patients with Duchenne muscular dystrophy amena-ble to exon 45 skipping. ClinicalTrials.gov Identifier: NCT02530905. Updated May 17, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02530905.

116. Sarepta Therapeutics Inc. Long-term, open-label extension study for patients with Duchenne muscular dystrophy enrolled in clinical trials evaluating casimersen or golodirsen. ClinicalTrials.gov Identifier: NCT03532542. Updated Dec 20, 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03532542.

117. PTC Therapeutics. A phase 2 study of the safety, pharmacokinetics, and pharmacodynamics of ataluren (PTC124®) in patients aged ≥2 to <5 years old with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT02819557. Updated Aug 28, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT02819557.

118. PTC Therapeutics. Phase 2, non-interventional, clinical study to assess dystrophin levels in subjects with nonsense mutation Duchenne muscular dystrophy who have been treated with ataluren for ≥ 9 months. ClinicalTrials.gov Identifier: NCT03796637. Updated Apr 10, 2020. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03796637.

119. PTC Therapeutics. An Open-Label Study Evaluating the Safety and Pharmacokinetics of Ataluren in Children From ≥6 Months to <2 Years of Age With Nonsense Mutation Duchenne Muscular Dystrophy. clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04336826 120. PTC Therapeutics. An open-label study for previously treated ataluren (PTC124®) pa-tients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01557400. Updated Nov 25, 2020. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT01557400.

121. PTC Therapeutics. An open-label, safety study for ataluren (PTC124) patients with nonsense mutation dystrophinopathy. ClinicalTrials.gov Identifier: NCT01247207. Updated Feb 16, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT01247207.

122. PTC Therapeutics. A phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of ataluren in patients with non-sense mutation Duchenne muscular dystrophy and open-label extension. ClinicalTrials.gov Identifier: NCT03179631. Updated Feb 8, 2022. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03179631.

123. Sarepta Therapeutics, Inc. An Open-Label, Systemic Gene Delivery Study Using Commercial Process Material to Evaluate the Safety of and Expression From SRP-9001 in Subjects With Duchenne Muscular Dystrophy (ENDEAVOR). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04626674

124. Sarepta Therapeutics, Inc. Systemic Gene Delivery Phase I/IIa Clinical Trial for Duchenne Muscular Dystrophy Using RAA-Vrh74.MHCK7.Micro-Dystrophin (MicroDys-IV-001). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03375164

125. Sarepta Therapeutics Inc. A multicenter, randomized, double-blind, placebo-controlled trial for Duchenne muscular dystrophy using SRP-9001. ClinicalTrials.gov Identifier: NCT03769116. Updated Dec 2021. Accessed Mar 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03769116.

126. Hoffmann-La Roche. A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulant Pa-tients With Spinal Muscular Atrophy. clinicaltrials.gov; 2022. Accessed September 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05115110

In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

Black and Hispanic adults with spina bifida or cerebral palsy are less likely to attend wellness visits than are White adults with the same pediatric-onset disabilities, a new study finds.

Black adults also had lower odds of having a bone density screening, compared with White adults. Plus, comorbidities were highest among the Black patients, according to the paper, which was published in Annals of Family Medicine.

Elham Mahmoudi, PhD, and her coauthors examined private insurance claims from 11,635 patients with cerebral palsy (CP) or spina bifida over ten years from 2007 to 2017. The researchers analyzed comorbidities and compared the rates of different psychological, cardiometabolic, and musculoskeletal conditions among these patients.

Only 23% of Hispanic participants and 18% of Black participants attended an annual wellness visit, compared with 32% of the White participants.

Only 1% of Black and 2% of White participants received any bone density screening (odds ratio = 0.54, 95% confidence interval [CI], 0.31-0.95), a service that is essential for catching a patient’s potential risk for osteoporosis and fractures.

According to the researchers, patients accessed services such as bone density scans, cholesterol assessments, diabetes screenings, and annual wellness visits less than recommended for people with those chronic conditions.

“People with spina bifida and cerebral palsy have complex care needs. We know through our work that chronic conditions are much higher among them compared with adults without disabilities,” Dr. Mahmoudi, associate professor in the department of family medicine at University of Michigan, Ann Arbor, said in an interview. “I was surprised to see even with private insurance, the rate of using preventative services is so low among White people and minority populations.”
 

Comorbidities highest in Black participants

Black adults had the highest comorbidity score of 2.5, and Hispanic adults had the lowest comorbidity score of 1.8. For White adults in the study, the comorbidity score was 2.0.

Osteoporosis, a common concern for people with spina bifida or cerebral palsy, was detected in around 4% of all participants. Osteoarthritis was detected in 13.38% of Black participants, versus 8.53% of Hispanic participants and 11.09% of White participants.

Diabetes and hypertension were more common among Black participants than among Hispanic and White participants. The percentages of Black patients with hypertension and diabetes were 16.5% and 39.89%, respectively. Among the Hispanic and White adults, the percentages with hypertension were 22.3% and 28.2%, respectively, according to the paper.
 

Disparities in access

Jamil Paden, racial and health equity manager at the Christopher and Dana Reeve Foundation, said getting access to literature, transportation, tables, chairs, weigh scales, and imaging equipment that accommodate the needs of people with disabilities are some of the biggest challenges for people with disabilities who are trying to receive care.

“It’s not a one size fits all, we have to recognize that if someone doesn’t see themselves in a particular place, then it makes it more challenging for them to feel comfortable speaking up and saying things about their health, which would prevent a person from saying something early on,” Mr. Paden said in an interview. “That particular issue will continue to grow and become more of a health risk, or health challenge down the line.”

Mr. Paden emphasized intersections between class, race, and circumstances which can, together, make health care less equitable for people with disabilities, especially in underserved communities and communities of color. He urged health care providers to distance their practices from a “one size fits all” approach to treatment and engage in their patients’ individual lives and communities.

“It’s not enough to just say, Hey, you have a disability. So let me treat your disability ... You have to recognize that although a patient may have a dire diagnosis, they also are a person of color, and they have to navigate different aspects of life from their counterparts,” he said.

Dr. Mahmoudi said patient and provider understanding of the disability is often lacking. She recommended advocating for patients, noting that giving both patients and providers the tools to further educate themselves and apply that to their regular visits is a good first step.

“Just having access to a facility doesn’t mean they will get the services they need. Preventative services that are recommended for people with disabilities differ from the general population. Providers should be educated about that and the patient needs to be educated about that,” she added.

“Patients who do not approach clinicians get lost in the system. Maybe many facilities are not disability friendly, or they need health literacy. If they don’t know they are at risk for osteoporosis, for example, then they won’t ask,” Dr. Mahmoudi said.

The study was funded by The National Institute on Disability, Independent Living, and Rehabilitation Research. Dr. Mahmoudi and Mr. Paden report no relevant financial relationships.

Black and Hispanic adults with spina bifida or cerebral palsy are less likely to attend wellness visits than are White adults with the same pediatric-onset disabilities, a new study finds.

Black adults also had lower odds of having a bone density screening, compared with White adults. Plus, comorbidities were highest among the Black patients, according to the paper, which was published in Annals of Family Medicine.

Elham Mahmoudi, PhD, and her coauthors examined private insurance claims from 11,635 patients with cerebral palsy (CP) or spina bifida over ten years from 2007 to 2017. The researchers analyzed comorbidities and compared the rates of different psychological, cardiometabolic, and musculoskeletal conditions among these patients.

Only 23% of Hispanic participants and 18% of Black participants attended an annual wellness visit, compared with 32% of the White participants.

Only 1% of Black and 2% of White participants received any bone density screening (odds ratio = 0.54, 95% confidence interval [CI], 0.31-0.95), a service that is essential for catching a patient’s potential risk for osteoporosis and fractures.

According to the researchers, patients accessed services such as bone density scans, cholesterol assessments, diabetes screenings, and annual wellness visits less than recommended for people with those chronic conditions.

“People with spina bifida and cerebral palsy have complex care needs. We know through our work that chronic conditions are much higher among them compared with adults without disabilities,” Dr. Mahmoudi, associate professor in the department of family medicine at University of Michigan, Ann Arbor, said in an interview. “I was surprised to see even with private insurance, the rate of using preventative services is so low among White people and minority populations.”
 

Comorbidities highest in Black participants

Black adults had the highest comorbidity score of 2.5, and Hispanic adults had the lowest comorbidity score of 1.8. For White adults in the study, the comorbidity score was 2.0.

Osteoporosis, a common concern for people with spina bifida or cerebral palsy, was detected in around 4% of all participants. Osteoarthritis was detected in 13.38% of Black participants, versus 8.53% of Hispanic participants and 11.09% of White participants.

Diabetes and hypertension were more common among Black participants than among Hispanic and White participants. The percentages of Black patients with hypertension and diabetes were 16.5% and 39.89%, respectively. Among the Hispanic and White adults, the percentages with hypertension were 22.3% and 28.2%, respectively, according to the paper.
 

Disparities in access

Jamil Paden, racial and health equity manager at the Christopher and Dana Reeve Foundation, said getting access to literature, transportation, tables, chairs, weigh scales, and imaging equipment that accommodate the needs of people with disabilities are some of the biggest challenges for people with disabilities who are trying to receive care.

“It’s not a one size fits all, we have to recognize that if someone doesn’t see themselves in a particular place, then it makes it more challenging for them to feel comfortable speaking up and saying things about their health, which would prevent a person from saying something early on,” Mr. Paden said in an interview. “That particular issue will continue to grow and become more of a health risk, or health challenge down the line.”

Mr. Paden emphasized intersections between class, race, and circumstances which can, together, make health care less equitable for people with disabilities, especially in underserved communities and communities of color. He urged health care providers to distance their practices from a “one size fits all” approach to treatment and engage in their patients’ individual lives and communities.

“It’s not enough to just say, Hey, you have a disability. So let me treat your disability ... You have to recognize that although a patient may have a dire diagnosis, they also are a person of color, and they have to navigate different aspects of life from their counterparts,” he said.

Dr. Mahmoudi said patient and provider understanding of the disability is often lacking. She recommended advocating for patients, noting that giving both patients and providers the tools to further educate themselves and apply that to their regular visits is a good first step.

“Just having access to a facility doesn’t mean they will get the services they need. Preventative services that are recommended for people with disabilities differ from the general population. Providers should be educated about that and the patient needs to be educated about that,” she added.

“Patients who do not approach clinicians get lost in the system. Maybe many facilities are not disability friendly, or they need health literacy. If they don’t know they are at risk for osteoporosis, for example, then they won’t ask,” Dr. Mahmoudi said.

The study was funded by The National Institute on Disability, Independent Living, and Rehabilitation Research. Dr. Mahmoudi and Mr. Paden report no relevant financial relationships.

Black and Hispanic adults with spina bifida or cerebral palsy are less likely to attend wellness visits than are White adults with the same pediatric-onset disabilities, a new study finds.

Black adults also had lower odds of having a bone density screening, compared with White adults. Plus, comorbidities were highest among the Black patients, according to the paper, which was published in Annals of Family Medicine.

Elham Mahmoudi, PhD, and her coauthors examined private insurance claims from 11,635 patients with cerebral palsy (CP) or spina bifida over ten years from 2007 to 2017. The researchers analyzed comorbidities and compared the rates of different psychological, cardiometabolic, and musculoskeletal conditions among these patients.

Only 23% of Hispanic participants and 18% of Black participants attended an annual wellness visit, compared with 32% of the White participants.

Only 1% of Black and 2% of White participants received any bone density screening (odds ratio = 0.54, 95% confidence interval [CI], 0.31-0.95), a service that is essential for catching a patient’s potential risk for osteoporosis and fractures.

According to the researchers, patients accessed services such as bone density scans, cholesterol assessments, diabetes screenings, and annual wellness visits less than recommended for people with those chronic conditions.

“People with spina bifida and cerebral palsy have complex care needs. We know through our work that chronic conditions are much higher among them compared with adults without disabilities,” Dr. Mahmoudi, associate professor in the department of family medicine at University of Michigan, Ann Arbor, said in an interview. “I was surprised to see even with private insurance, the rate of using preventative services is so low among White people and minority populations.”
 

Comorbidities highest in Black participants

Black adults had the highest comorbidity score of 2.5, and Hispanic adults had the lowest comorbidity score of 1.8. For White adults in the study, the comorbidity score was 2.0.

Osteoporosis, a common concern for people with spina bifida or cerebral palsy, was detected in around 4% of all participants. Osteoarthritis was detected in 13.38% of Black participants, versus 8.53% of Hispanic participants and 11.09% of White participants.

Diabetes and hypertension were more common among Black participants than among Hispanic and White participants. The percentages of Black patients with hypertension and diabetes were 16.5% and 39.89%, respectively. Among the Hispanic and White adults, the percentages with hypertension were 22.3% and 28.2%, respectively, according to the paper.
 

Disparities in access

Jamil Paden, racial and health equity manager at the Christopher and Dana Reeve Foundation, said getting access to literature, transportation, tables, chairs, weigh scales, and imaging equipment that accommodate the needs of people with disabilities are some of the biggest challenges for people with disabilities who are trying to receive care.

“It’s not a one size fits all, we have to recognize that if someone doesn’t see themselves in a particular place, then it makes it more challenging for them to feel comfortable speaking up and saying things about their health, which would prevent a person from saying something early on,” Mr. Paden said in an interview. “That particular issue will continue to grow and become more of a health risk, or health challenge down the line.”

Mr. Paden emphasized intersections between class, race, and circumstances which can, together, make health care less equitable for people with disabilities, especially in underserved communities and communities of color. He urged health care providers to distance their practices from a “one size fits all” approach to treatment and engage in their patients’ individual lives and communities.

“It’s not enough to just say, Hey, you have a disability. So let me treat your disability ... You have to recognize that although a patient may have a dire diagnosis, they also are a person of color, and they have to navigate different aspects of life from their counterparts,” he said.

Dr. Mahmoudi said patient and provider understanding of the disability is often lacking. She recommended advocating for patients, noting that giving both patients and providers the tools to further educate themselves and apply that to their regular visits is a good first step.

“Just having access to a facility doesn’t mean they will get the services they need. Preventative services that are recommended for people with disabilities differ from the general population. Providers should be educated about that and the patient needs to be educated about that,” she added.

“Patients who do not approach clinicians get lost in the system. Maybe many facilities are not disability friendly, or they need health literacy. If they don’t know they are at risk for osteoporosis, for example, then they won’t ask,” Dr. Mahmoudi said.

The study was funded by The National Institute on Disability, Independent Living, and Rehabilitation Research. Dr. Mahmoudi and Mr. Paden report no relevant financial relationships.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.

In a rare second review of a new drug application, a Food and Drug Association advisory panel has voted to recommend approval of a novel drug to treat amyotrophic lateral sclerosis (ALS).

By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.

The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.

This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.

“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.

“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
 

A rare second chance

ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.

The FDA has approved two therapies for ALS, but both have limited efficacy.

Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.

Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.

Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.

The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).

In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.

The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.

An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.

However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.

“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.

Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.

They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.

“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.

Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.

“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.

Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
 

A challenging situation

Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.

“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.

However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”

In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.

“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.

If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.

“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.

Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”

A version of this article first appeared on Medscape.com.